DE69929704T2 - TETRAHYDROBENZAZEPINE DERIVATIVES USE AS DOPAMINE D3 RECEPTOR MODULATORS (ANTIPSYCHOTIC AGENTS) - Google Patents

Description

The present invention relates to novel tetrahydrobenzazepine derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy as modulators of dopamine D ₃ receptors, in particular as antipsychotic agents.

wobei

ein gegebenenfalls substituierter Thienyl- oder gegebenenfalls substituierter Phenylring ist; R¹, R² und R³ jeweils unter anderem ein Wasserstoffatom darstellen; X unter anderem einen Rest (CH₂)_mNR⁷CO darstellt; m 2-4 ist; und Ar¹ einen gegebenenfalls substituierten heterocyclischen Ring oder einen gegebenenfalls substituierten Phenylring darstellt. Für die Verbindungen wird angegeben, dass sie als antiarrhytmische Mittel geeignet sind.U.S. Patent No. 5,294,621 describes tetrahydropyridine derivatives of the formula

in which

an optionally substituted thienyl or optionally substituted phenyl ring; R ¹ , R ² and R ³ each represent, inter alia, a hydrogen atom; X represents inter alia a radical (CH ₂ ) _m NR ⁷ CO; m is 2-4; and Ar ^{1 represents} an optionally substituted heterocyclic ring or an optionally substituted phenyl ring. The compounds are stated to be useful as antiarrhythmic agents.

wobei R OR³, NR⁴R⁵ oder N(OR⁴)R⁵ darstellt, R⁴ und R⁵ unter anderem ein Wasserstoffatom, einen Niederalkyl-, Aroyl- oder Heteroaroylrest darstellen; m null, 1 oder 2 ist; R¹ ein Wasserstoffatom, Aryl- oder verschiedene Heteroarylreste darstellt; n null oder 1-4 ist und R² die Reste

darstellt. Für die Verbindungen wird angegeben, dass sie antidopaminerge Mittel sind, die als antipsychotische und antihypertensive Mittel geeignet sind und auch bei der Behandlung von mit Hyperprolactinämie verwandten Zuständen und einigen Störungen des zentralen Nervensystems von Nutzen sind.EP-A-0 431,580 describes compounds of the formula

wherein R represents OR ³ , NR ⁴ R ⁵ or N (OR ⁴ ) R ⁵ , R ⁴ and R ^{5 represent,} inter alia, a hydrogen atom, a lower alkyl, aroyl or heteroaroyl group; m is zero, 1 or 2; R ^{1 represents} a hydrogen atom, aryl or various heteroaryl radicals; n is zero or 1-4 and R ^{2 is} the radicals

represents. The compounds are stated to be antidopaminergic agents which are useful as antipsychotic and antihypertensive agents and are also useful in the treatment of hyperprolactinemia-related conditions and some central nervous system disorders.

WHERE 95/10513 describes benzothiophene derivatives and related compounds as an estrogen antagonist.

WO 97/43262 and WO 98/06699 describe that tetrahydroisoquinoline derivatives have an affinity for the dopamine D ₃ receptor.

We have now found a class of tetrahydrobenzazepine derivatives that have an affinity for dopamine receptors; in particular the D ₃ receptor, and thus a potential for the treatment of conditions in which modulation of the D ₃ receptor is advantageous, eg in antipsychotic agents.

Formel (I) wobei:
R¹ einen Substituenten darstellt, ausgewählt aus einem Wasserstoff- oder Halogenatom, einem Hydroxy-, Cyano-, Nitro-, Trifluormethyl-, Trifluormethoxy-, Trifluormethansulfonyloxy-, Pentafluorethyl-, C_1-4-Alkyl-, C_1-4-Alkoxy-, Aryl-C_1-4-alkoxy-, C_1-4-Alkylthio-, C_1-4-Alkoxy-C_1-4-alkyl-, C_3-6-Cycloalkyl-C_1-4-alkoxy-, C_1-4-Alkanoyl-, C_1-4-Alkoxycarbonyl-, C_1-4-Alkylsulfonyl-, C_1-4-Alkylsulfonyloxy-, C_1-4-Alkylsulfonyl-C_1-4-alkyl-, Arylsulfonyl-, Arylsulfonyloxy-, Arylsulfonyl-C_1-4-alkyl-, C_1-4-Alkylsulfonamido-, C_1-4-Alkylamido-, C_1-4-Alkylsulfonamido-C_1-4-alkyl-, C_1-4-Alkylamido-C_1-4-alkyl-, Arylsulfonamido-, Arylcarboxamido-, Arylsulfonamido-C_1-4-alkyl-, Arylcarboxamido-C_1-4-alkyl-, Aroyl-, Aroyl-C_1-4-alkyl- oder Aryl-C_1-4-alkanoylrest; einem Rest R³OCO(CH₂)_p, R³CON(R⁴)(CH₂)_p, R³R⁴NCO(CH₂)_p, oder R³R⁴NSO₂(CH₂)_p, wobei R³ und R⁴ jeweils unabhängig ein Wasserstoffatom oder einen C_1-4-Alkylrest darstellen oder R³R⁴ Teil eines C_3-6-Azacycloalkan- oder C_3-6-(2-Oxo)azacyloalkanrings bildet und p null oder eine ganze Zahl von 1 bis 4 darstellt; oder einem Rest Ar³-Z, wobei Ar³ einen Phenylring oder einen 5- oder 6-gliedrigen aromatischen, heterocyclischen Ring darstellt, wobei diese jeweils gegebenenfalls mit einem oder mehreren Substituenten substituiert sind, ausgewählt aus Wasserstoff, Halogen, Amino, Cyano, C_1-4-A1kyl, C_1-4-Alkylamino, C_1-4-Dialkylamino, C_1-4-Alkylamido, C_1-4-Alkanoyl oder R⁵R⁶NCO, wobei R⁵ und R⁶ jeweils unabhängig ein Wasserstoffatom oder einen C_1-4-Alkylrest darstellen und Z eine Bindung, O, S oder CH₂ darstellt;
R² ein Wasserstoffatom oder einen C_1-4-Alkylrest darstellt;
q 1 oder 2 ist;
A einen Rest der Formel (a), (b), (c) oder (d) darstellt;

wobei:
Ar einen Phenylring oder einen 5- oder 6-gliedrigen aromatischen, heterocyclischen Ring oder ein bicyclisches Ringsystem darstellt, wobei diese alle unabhängig gegebenenfalls mit einem oder mehreren Substituenten substituiert sind, ausgewählt aus einem Wasserstoff- oder Halogenatom oder einem Hydroxy-, Oxo-, Cyano-, Nitro-, Trifluormethyl-, C_1-4-Alkyl-, C_1-4-Alkoxy-, C_1-4-Alkylendioxy-, C_1-4-Alkanoyl-, C_1-4-Alkylsulfonyl-, C_1-4-Alkylsulfinyl-, C_1-4-Alkylthio-, R⁷SO₂N(R⁸)-, R⁷R⁸NSO₂-, R⁷R^BN-, R⁷R⁸NCO- oder R⁷CON(R⁸)-Rest, wobei R⁷ und R⁸ jeweils unabhängig ein Wasserstoffatom oder einen C_1-4-Alkylrest darstellen, oder R⁷R⁸ zusammen eine C_3-6-Alkylenkette bilden und wobei in dem Ring Ar jene Substituenten, die in ortho-Stellung zueinander stehen, gegebenenfalls verbunden sind, um einen 5- oder 6-gliedrigen Ring zu bilden;
Ar¹ und Ar² jeweils unabhängig einen Phenylring oder einen 5- oder 6-gliedrigen aromatischen, heterocyclischen Ring darstellen, wobei diese jeweils unabhängig gegebenenfalls mit einem oder mehreren Substituienten substituiert sind, ausgewählt aus einem Wasserstoff- oder Halogenatom oder einem Hydroxy-, Oxo-, Cyano-, Nitro-, Trifluormethyl-, C_1-4-Alkyl-, C_1-4-Alkoxy-, C_1-4-Alkylendioxy-, C_1-4-Alkanoyl-, C_1-4-Alkylsulfonyl-, C_1-4-Alkylsulfinyl-, C_1-4-Alkylthio-, R⁷SO₂N(R⁸)-, R⁷R⁸NSO₂-, R⁷R⁸N-, R⁷R⁸NCO- oder R⁷CON(R⁸)-Rest, wobei R⁷ und R⁸ wie vorstehend definiert sind; und wobei in dem Ring Ar² jene Substituenten, die in ortho-Stellung zueinander stehen, gegebenenfalls verbunden sind, um einen 5- oder 6-gliedrigen Ring zu bilden;
Y eine Bindung, -NHCO-, -CONH-, -CH₂- oder -(CH₂)_mY¹(CH₂)_n- darstellt, wobei Y¹ O, S, SO₂ oder CO darstellt, und m und n jeweils null oder 1 darstellen, derart dass die Summe von m + n null oder 1 ist, mit der Maßgabe, dass, wenn A einen Rest der Formel (a) darstellt, jeder in Ar in ortho-Stellung zur Carboxamideinheit vorhandene Substituent notwendigerweise Wasserstoff oder eine Methoxygruppe ist;
r und s unabhängig eine ganze Zahl von null bis 3 darstellen, derart dass die Summe von r und s gleich einer ganzen Zahl von 1 bis 4 ist;
V eine Bindung, O oder S darstellt;
und Salze davon.In a first embodiment, the present invention provides compounds of formula (I):

Formula (I) wherein:
R ^{1 represents} a substituent selected from a hydrogen or halogen atom, a hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethanesulfonyloxy, pentafluoroethyl, C _1-4 alkyl, C _1-4 alkoxy -, aryl-C _1-4 -alkoxy, C _1-4 -alkylthio, C _1-4 -alkoxy-C _1-4 -alkyl, C _3-6 -cycloalkyl-C _1-4 -alkoxy, C _1-4 alkanoyl, C _1-4 alkoxycarbonyl, C _1-4 alkylsulfonyl, C _1-4 alkylsulfonyloxy, C _1-4 alkylsulfonylC _1-4 alkyl, arylsulfonyl, Arylsulfonyloxy, arylsulfonylC _1-4 alkyl, C _1-4 alkylsulfonamido, C _1-4 alkylamido, C _1-4 alkylsulfonamidoC _1-4 alkyl, C _1-4 alkylamido C _1-4 -alkyl-, arylsulfonamido, arylcarboxamido, arylsulfonamido-C _1-4 -alkyl-, arylcarboxamido-C _1-4 -alkyl-, aroyl-, aroyl-C _1-4 -alkyl- or aryl- C _1-4 alkanoyl radical; a radical R ³ OCO (CH ₂ ) _p , R ³ CON (R ⁴ ) (CH ₂ ) _p , R ³ R ⁴ NCO (CH ₂ ) _p , or R ³ R ⁴ NSO ₂ (CH ₂ ) _p , where R Each of R ³ and R ⁴ independently represents a hydrogen atom or a C _1-4 alkyl radical, or R ³ R ^{4 forms} part of a C _3-6 azacycloalkane or C _3-6 (2-oxo) azacyloalkane ring and p represents zero or one whole Number from 1 to 4; or a group Ar ³ -Z, wherein Ar ^{3 represents} a phenyl ring or a 5- or 6-membered aromatic heterocyclic ring, each of which is optionally substituted with one or more substituents selected from hydrogen, halogen, amino, cyano, C _1-4 alkyl, C _1-4 alkylamino, C _1-4 dialkylamino, C _1-4 alkylamido, C _1-4 alkanoyl or R ⁵ R ⁶ NCO, wherein R ⁵ and R ⁶ each independently represent a hydrogen atom or a C _1-4 alkyl radical and Z represents a bond, O, S or CH ₂ ;
R ^{2 represents} a hydrogen atom or a C _1-4 alkyl radical;
q is 1 or 2;
A represents a group of formula (a), (b), (c) or (d);

in which:
Ar represents a phenyl ring or a 5- or 6-membered aromatic heterocyclic ring or a bicyclic ring system, all of which are independently independently optionally substituted with one or more substituents selected from a hydrogen or halogen atom or a hydroxy, oxo, cyano -, nitro, trifluoromethyl, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylenedioxy, C _1-4 alkanoyl, C _1-4 alkylsulfonyl, C _{1 -4-} alkylsulfinyl, C _1-4 -alkylthio, R ⁷ SO ₂ N (R ⁸ ) -, R ⁷ R ⁸ NSO ₂ -, R ⁷ R ^B N-, R ⁷ R ⁸ NCO- or R ⁷ CON (R ⁸ ) radical, wherein R ⁷ and R ⁸ each independently represent a hydrogen atom or a C _1-4 alkyl radical, or R ⁷ R ⁸ together form a C _3-6 alkylene chain and wherein in the ring Ar those substituents which are ortho to each other, optionally joined to form a 5- or 6-membered ring;
Ar ¹ and Ar ² each independently represent a phenyl ring or a 5- or 6-membered aromatic heterocyclic ring, each independently optionally substituted with one or more substituents selected from a hydrogen or halogen atom or a hydroxy, oxo , Cyano, nitro, trifluoromethyl, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylenedioxy, C _1-4 alkanoyl, C _1-4 alkylsulfonyl, C _1-4 alkylsulfinyl, C _1-4 alkylthio, R ⁷ SO ₂ N (R ⁸ ) -, R ⁷ R ⁸ NSO ₂ -, R ⁷ R ⁸ N-, R ⁷ R ⁸ NCO- or R ⁷ CON (R ⁸ ) radical, wherein R ⁷ and R ^{8 are} as defined above; and in the ring Ar ^2, those substituents which are ortho to each other are optionally linked to form a 5- or 6-membered ring;
Y represents a bond, -NHCO-, -CONH-, -CH ₂ - or - (CH ₂ ) _m Y ¹ (CH ₂ ) _n -, wherein Y ^{1 represents} O, S, SO ₂ or CO, and m and n each represent zero or 1 such that the sum of m + n is zero or one, with the proviso that when A represents a group of formula (a), any substituent present in Ar ortho to the carboxamide moiety will necessarily be hydrogen or is a methoxy group;
r and s independently represent an integer of zero to 3 such that the sum of r and s is equal to an integer of 1 to 4;
V represents a bond, O or S;
and salts thereof.

In The above compounds of the formula (I) may be an alkyl group or an alkyl moiety may be straight chain or branched. alkyl, which can be used shut down Methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl and n-heptyl groups and any branched isomers thereof, such as isopropyl, t-butyl, sec-butyl groups and the like.

When R ^{1 is} an aryl C _1-4 alkoxy, arylsulfonyl, arylsulfonyloxy, arylsulfonylC _1-4 alkyl, arylsulfonamido, arylcarboxamido, arylsulfonamidoC _1-4 alkyl, arylcarboxamido C _{1 4} -alkyl, aroyl, aroyl-C _1-4 -alkyl or aryl-C _1-4 alkanoyl, the aryl moiety may be selected from an optionally substituted phenyl ring or an optionally substituted 5- or 6-membered heterocyclic ring be. In the radical R ¹ , the aryl moiety may optionally be substituted by one or more substituents selected from hydrogen, halogen, amino, cyano, C _1-4 alkyl, C _1-4 alkylamino, C _1-4 dialkylamino, C _1-4 alkylamido, C _1-4 alkanoyl or a radical R ⁵ R ⁶ NCO are selected, wherein R ⁵ and R ⁶ independently represent a hydrogen atom or a C _1-4 alkyl radical.

at the halogen atom present in the compounds of formula (I) is, it may be fluorine, chlorine, bromine or iodine.

When q is 2, the substituents R ¹ may be the same or different.

An optionally substituted 5- or 6-membered heterocyclic aromatic ring as defined for any of Ar, Ar ¹ , Ar ² or Ar ³ may be from 1 to 4 heteroatoms selected from O, N or S, contain. When the ring contains 2-4 heteroatoms, one is preferably selected from O, N and S and the remaining heteroatoms are preferably N. Examples of 5- and 6-membered heterocyclic radicals include furyl, thienyl, pyrrolyl, oxazolyl, Thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazyl, pyrimidinyl, pyrazolyl, isothiazolyl and isoxazolyl groups.

Examples for bicyclic Ring systems, for example bicyclic aromatic or heteroaromatic ring systems, for Ar shut down Naphthyl, indazolyl, indolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzimidazolyl, Benzoxazolyl, benzisoxazolyl, benzisothiazolyl, quinolinyl, Quinoxolinyl, quinazolinyl, cinnolinyl, isoquinolinyl, pyrazolo [1,5-a] pyrimidyl, Pyrrolo [3,2-b] pyridyl, pyrrolo [3,2-c] pyridyl, thieno [3,2-b] thiophenyl, 1,2-dihydro-2-oxoquinolinyl, 3,4-dihydro-3-oxo-2H-benzoxazinyl and 1,2-dihydro-2-oxo-3H-indolyl radicals.

The rings Ar, Ar ¹ or Ar ² may independently of one another optionally be substituted by one or more substituents selected from: a hydrogen atom or halogen atom, a hydroxy, oxo, cyano, nitro, trifluoromethyl, C _{1 4-} alkyl, C _1-4 -alkoxy, C _1-4 -alkylenedioxy, C _1-4 -alkanoyl, C _1-4 -alkylsulfonyl, C _1-4 -alkylsulfinyl, C _1-4 Alkylthio, R ⁷ SO ₂ N (R ⁸ ) -, R ⁷ R ⁸ NSO ₂ -, R ⁷ R ⁸ N, R ⁷ R ⁸ NCO or R ⁷ CON (R ⁸ ) radical, where each radical of R ⁷ and R ⁸ independently represent a hydrogen atom or a C _1-4 alkyl radical, or R ⁷ R ⁸ together form a C _3-6 alkylene chain.

Alternatively, Ar and Ar ^{2 may} optionally be substituted by one or more 5- or 6-membered heterocyclic rings, as defined above, optionally substituted by a C _1-2 alkyl radical or by an R ⁷ R ⁸ N radical wherein R ⁷ and R ^{8 are} as defined above.

In the rings Ar and Ar ² , substituents which are ortho to each other may be linked together to form a 5- or 6-membered ring.

It understands that for the use in medicine the salts of formula (I) physiologically compatible should be. Suitable physiologically acceptable salts are for a Skilled in the art and include, for example, acid addition salts one containing inorganic acids, e.g. Hydrochloric, hydrobromic, sulfuric, nitric or Phosphoric acid, and organic acids, e.g. Amber, malein, vinegar, fumar, lemon, wine, benzoin, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid are formed. Other not physiologically compatible Salts, e.g. Oxalates can used, for example the isolation of the compounds of formula (I) and are in scope of this invention included. Likewise, within the scope of the invention Solvates and hydrates of the compounds of formula (I) included.

Certain Compounds of formula (I) can Acid addition salts with one or more equivalents the acid form. The present invention includes within its scope all possible stoichiometric and non-stoichiometric Molds.

The Compounds of formula (I) can with regard to the configuration on the cyclohexyl ring in the mold the cis and trans isomers are present. If A is a group (c), can the compounds also as geometric isomers around the double bond available. The present invention includes in its scope all such Isomers, including of the mixtures. Preferably, the compounds of the invention are with regard to the configuration on the cyclohexyl ring in the mold the trans configuration before. For connections of the formula (I) in which A represents a group (c), the trans geometry of the double bond is preferred.

In compounds of formula (I), it is preferred that R ^{1 represents} a substituent selected from: a halogen atom, methyl, cyano, acetyl, trifluoromethyl, pentafluoroethyl, methylsulfonyl, methylsulfonyloxy or trifluoromethoxy group. Alternatively, it is preferred that R ^{1 is} Ar ³ Z, where Z is a bond and Ar ^{3 is} a 5- or 6-membered ring heterocycle optionally substituted by a methyl group and containing at least one N and one O atom , Preferably, q is 1. R ² is preferably a hydrogen atom.

If the group A is a group of formula (a), preferred Examples of Ar is an optionally substituted phenyl, indolyl, Pyrazolo [1,5-a] pyrimidyl, cinnolinyl, quinolinyl, benzo [b] furanyl or pyrrolopyridyl radical.

When the group A is a group of the formula (b), preferred examples of Ar ¹ include an optionally substituted phenyl radical, Y is preferably a bond, and preferred examples of Ar ² include an optionally substituted phenyl, pyridyl, pyrimidinyl, isoxazolyl -, oxazolyl or Oxadiazolylrest a.

If the group A is a group of formula (c), close preferred Examples of Ar is an optionally substituted phenyl radical one.

It is also preferred that the rings Ar, Ar ¹ or Ar ^{2 are} independently optionally substituted by one or more substituents selected from: a hydrogen atom or halogen atom, cyano, methoxy, trifluoromethyl, methylenedioxy, acetyl , Acetylamino, methylsulfonyl, methylsulfonyloxy, methylaminosulfonyl, methylsulfonylamino or methylaminocarbonyl group.

Certain of the substituted heteroaromatic ring systems used in the compounds of formula (I) may be in one or more present tautomeric forms.

The present invention includes all such tautomeric forms in their scope, including Mixtures.

Individual compounds of the invention include those specifically exemplified and named below:
trans-3- (2- (1- (4- (4-quinolinyl) carboxamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine;
trans- (E) -3- (2- (1- (4- (3- (3-Methylsulfonyl) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine;
trans- (E) -3- (2- (1- (4- (3- (4-fluoro) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine;
trans-3- (2- (1- (4- (2-indolyl) carboxamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine;
trans-3- (2- (1- (4- (3- (3-Pyridyl) phenyl) carboxamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine;
trans-3- (2- (1- (4-Phenylacetamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine;
trans-3- (2- (1- (4- (3-indolyl) acetamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine;
trans-3- (2- (1- (4- (4-Quinolinyl) acetamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine;
trans- (E) -3- (2- (1- (4- (3- (4-fluoro) phenylpropenoyl) amino) cyclohexyl) ethyl) -6-methoxy-2,3,4,5-tetrahydro-1H- -3-benzazepine;
trans-6-methoxy-3- (2- (1- (4- (4-quinolinyl) carboxamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine;
trans-6-methoxy-3- (2- (1- (4- (3-pyrrolo [2,3-b] pyridyl) carboxamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine;
trans- (E) -7-Cyano-3- (2- (1- (4- (3- (4-fluoro) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine;
trans-7-cyano-3- (2- (1- (4- (3-pyrrolo [2,3-b] pyridyl) carboxamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3 benzazepine;
trans-7-cyano-3- (2- (1- (4- (3- (3- (5-methyl) -1,2,4-oxadiazolyl) benzoyl) amino) cyclohexyl) ethyl) -2,3, 4,5-tetrahydro dro-1H-3-benzazepine;
trans- (E) -7-Cyano-3- (2- (1- (4- (5-quinolinyl) carboxamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-benzazepine;
trans- (E) -7-Cyano-3- (2- (1- (4- (3- (3-acetylamino) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine;
trans-7-cyano-3- (2- (1- (4- (6- (3,4-dihydro-3-oxo) -2H-benzoxazinyl) carboxamido) cyclohexyl) ethyl) -2,3,4,5 tetrahydro-1H-benzazepine;
trans- (E) -7-Cyano-3- (2- (1- (4- (3- (6- (1,2-dihydro-2-oxo) quinolinyl) propenyl) amino) cyclohexyl) ethyl) -2 , 3,4,5-tetrahydro-1H-3-benzazepine;
trans- (E) -7-Cyano-3- (2- (1- (4- (3- (2-fluoro-4-acetylamino) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5- tetrahydro-1H-3-benzazepine;
trans- (E) -7-Cyano-3- (2- (1- (4- (3- (8- (1,2-dihydro-2-oxo) quinolinyl) propenoyl) amino) cyclohexyl) ethyl) -2 , 3,4,5-tetrahydro-1H-3-benzazepine;
trans-7-cyano-3- (2- (1- (4- (5- (8-fluoro) quinolinyl) carboxamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine;
trans-7-Acetyl-3- (2- (1- (4- (5-quinolinyl) carboxamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine;
trans-3- (2- (1- (4- (5- (2-methyl) quinolinyl) carboxamido) cyclohexyl) ethyl) -7-methylsulphonyl-2,3,4,5-tetrahydro-1H-3-benzazepine;
trans-3- (2- (1- (4- (3- (3- (5-Methyl) -1,2,4-oxadiazolyl) benzoyl) amino) cyclohexyl) ethyl) -7-methylsulfonyl-2,3, 4,5-tetrahydro-1H-3-benzazepine;
trans-7- (5- (3-Methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (3-pyrrolo [2,3-b] pyridyl) carboxamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine;
trans- (E) -7- (3- (5-Methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (3- (4-fluoro) phenylpropenoyl) amino) cyclohexyl ) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine;
trans- (E) -7- (5- (3-Methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (3- (4-fluoro) phenylpropenoyl) amino) cyclohexyl ) ethyl) -2,3; 4,5-tetrahydro-1H-3-benzazepine;
trans- (E) -7- (5- (3-Methyl) isoxazolyl) -3- (2- (1- (4- (3- (4-fluoro) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3 , 4,5-tetrahydro-1H-3-benzazepine;
trans-7- (5- (3-Methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (4-fluoro) phenylacetamido) cyclohexyl) ethyl) -2,3,4 , 5-tetrahydro-1H-3-benzazepine;
trans-7-cyano-3- (2- (1- (4- (2,5-difluoro) phenylacetamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine;
trans-7-cyano-3- (2- (1- (2-naphthylacetamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine;
trans- (E) -7-Cyano-3- (2- (1- (4- (3- (2,4-difluoro) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro- 1H-3-benzazepine;
trans- (E) -7-Cyano-3- (2- (1- (4- (3- (2,5-difluoro) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro- 1H-3-benzazepine;
trans- (E) -7-Cyano-3- (2- (1- (4- (3- (3-fluoro) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine;
trans-7-cyano-3- (2- (1- (4- (3-phenylpropanoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine;
trans- (E) -7-Cyano-3- (2- (1- (4- (3- (2-fluoro) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine;
trans-7-cyano-3- (2- (1- (4- (8- (1,4-dihydro-4-oxo) quinolinyl) carboxamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro- 1H-3-benzazepine;
trans-7-cyano-3- (2- (1- (4- (2-naphthyl) carboxamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine;
trans- (E) -7-Cyano-3- (2- (1- (4- (3- (2-methoxy) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine;
trans- (E) -7-Cyano-3- (2- (1- (4- (3- (3-methoxy) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine;
trans- (E) -7-Cyano-3- (2- (1- (4- (3- (4-methoxy) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine;
trans- (E) -7-Cyano-3- (2- (1- (4- (3- (2-acetyl) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine;
trans- (E) -7-Cyano-3- (2- (1- (4- (3- (4-acetyl) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine;
trans- (E) -7-Cyano-3- (2- (1- (4- (3- (2-cyano) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine;
trans- (E) -7-Cyano-3- (2- (1- (4- (3- (3-cyano) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine;
trans-7-cyano-3- (2- (1- (4- (3- (5- (3-methyl) isoxazolyl) benzoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1 H -3-benzazepine;
trans-7-cyano-3- (2- (1- (4- (7- (1,2-dihydro-2-oxo) quinolinyl) carboxamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro dro-1H-3-benzazepine;
trans (Z) -7-Cyano-3- (2- (1- (4- (3-phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine
trans- (E) -7-Cyano-3- (2- (1- (4- (3- (2-pyridyl) propenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine;
trans- (E) -7-Cyano-3- (2- (1- (4- (3- (1- (4-fluoro) naphthyl) propenoyl) amino) cyclohexyl) ethyl) -2,3,4,5 tetrahydro-1H-3-benzazepine;
trans- (E) -7-Cyano-3- (2- (1- (4- (3- (6-benzodioxanyl) propenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine;
trans- (E) -7-Cyano-3- (2- (1- (4- (3- (3- (5-fluoro) indolyl) propenoyl) amino) cyclohexyl) ethyl) -2,3,4,5 tetrahydro-1H-3-benzazepine;
trans- (E) -7-Cyano-3- (2- (1- (4- (3- (3- (1-methyl) benzimidazolyl) propenoyl) amino) cyclohexyl) ethyl) -2,3,4,5 tetrahydro-1H-3-benzazepine;
trans- (E) -7-Cyano-3- (2- (1- (4- (3- (7-benzofuranyl) propenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine;
trans- (E) -7-Cyano-3- (2- (1- (4- (3- (5- (3-methyl) indolyl) propenoyl) amino) cyclohexyl) ethyl) -2,3,4,5 tetrahydro-1H-3-benzazepine;
trans- (E) -7-Cyano-3- (2- (1- (4- (3- (6- (2,3-dihydro-2-oxo) indolyl) propenoyl) amino) cyclohexyl) ethyl) -2 , 3,4,5-tetrahydro-1H-3-benzazepine;
trans-7-cyano-3- (2- (1- (2-benzofuranylacetamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine;
trans- (E) -7-Cyano-3- (2- (1- (4- (3- (4- (2-methyl) indolyl) propenoyl) amino) cyclohexyl) ethyl) -2,3,4,5 tetrahydro-1H-3-benzazepine;
trans- (E) -7-Cyano-3- (2- (1- (4- (3- (5-benzimidazolyl) propenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine;
trans- (E) -7-Cyano-3- (2- (1- (4- (3-phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine;
trans- (E) -7-Cyano-3- (2- (1- (4- (3- (2,3-methylenedioxy) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro- 1H-3-benzazepine;
trans- (E) -7-Cyano-3- (2- (1- (4- (3- (3- (1- (2-oxo) pyrrolidinyl)) phenylpropenoyl) amino) cyelohexyl) ethyl) -2,3 , 4,5-tetrahydro-1H-3-benzazepine;
trans-7-cyano-3- (2- (1- (4- (2-indolylacetamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine;
trans-7-cyano-3- (2- (1- (4- (2-benzothiophenylacetamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine;
trans- (E) -7-Cyano-3- (2- (1- (4- (3- (2- (3-bromo) thiophenyl) propenoyl) amino) cyclohexyl) ethyl) -2,3,4,5 tetrahydro-1H-3-benzazepine;
trans-7-cyano-3- (2- (1- (4- (3- (2-pyridyl) benzoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine;
trans-7-cyano-3- (2- (1- (4- (3- (5-pyrimidinyl) benzoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine;
trans-7-cyano-3- (2- (1- (4- (3- (4-cyanophenyl) benzoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine;
trans-7-cyano-3- (2- (1- (4- (3- (3- (5-ethyl) -1,2,4-oxadiazolyl) benzoyl) amino) cyclohexyl) ethyl) -2,3, 4,5-tetrahydro-1H-3-benzazepine;
trans- (E) -7-Cyano-3- (2- (1- (4- (3- (2-thiophenyl) propenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine;
trans- (E) -7-Cyano-3- (2- (1- (4- (3- (2-furanyl) propenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine;
trans- (E) -7-Cyano-3- (2- (1- (4- (3- (3-thiophenyl) propenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine;
trans- (E) -7-Cyano-3- (2- (1- (4- (3- (3-furanyl) propenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine;
trans- (E) -7-Cyano-3- (2- (1- (4- (3- (4-quinolinyl) propenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine;
trans- (E) -7-Cyano-3- (2- (1- (4- (3- (5-pyrimidinyl) propenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine;
trans-7-cyano-3- (2- (1- (4- (2,4-difluoro) phenylacetamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine;
trans-7-cyano-3- (2- (1- (4- (1-naphthyl) acetamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine;
trans-7-Actyl-3- (2- (1- (4- (3-pyrrolo [2,3-b] pyridyl) carboxamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3 benzazepine;
trans-7-Actyl-3- (2- (1- (4- (4-fluoro) phenylacetamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine;
trans-7-Actyl-3- (2- (1- (4- (3- (3- (5-methyl) -1,2,4-oxadiazolyl) benzoyl) amino) cyclohexyl) ethyl) -2,3, 4,5-tetrahydro dro-1H-3-benzazepine;
trans- (E) -7-Actyl-3- (2- (1- (4- (3- (4-fluoro) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine;
trans-7-cyano-3- (2- (1- (4- (6- (2-amino) benzothiazolyl) acetamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine;
trans-7-cyano-3- (2- (1- (4- (6- (2-methyl) benzothiazolyl) acetamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine;
trans-7-cyano-3- (2- (1- (4- (6- (2,3-dihydro-2-oxo) indolyl) acetamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro- 1H-3-benzazepine;
trans-7-cyano-3- (2- (1- (4- (5- (2,3-dihydro-2-oxo) indolyl) acetamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro- 1H-3-benzazepine;
trans- (E) -7-Cyano-3- (2- (1- (4- (3- (4-methylaminocarbonyl) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine;
trans-7-cyano-3- (2- (1- (4- (5- (2-amino) benzoxazolyl) acetamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine;
trans-7-cyano-3- (2- (1- (4- (6- (1,2-dihydro-2-oxo) quinolinyl) acetamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro- 1H-3-benzazepine;
trans-7-cyano-3- (2- (1- (4- (7- (1,2-dihydro-2-oxo) quinolinyl) acetamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro- 1H-3-benzazepine;
trans- (E) -7-Acetyl-3- (2- (1- (4- (3- (3-methoxy) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine;
trans- (E) -7-Acetyl-3- (2- (1- (4- (3- (2-cyano) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine;
trans- (E) -7-Acetyl-3- (2- (1- (4- (3- (3-thiophenyl) propenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine;
trans- (E) -7-Acetyl-3- (2- (1- (4- (3- (8- (1,2-dihydro-2-oxo) quinolinyl) propenoyl) amino) cyclohexyl) ethyl) -2 , 3,4,5-tetrahydro-1H-3-benzazepine;
trans-7-cyano-3- (2- (1- (4- (3- (1-pyrazolyl) benzoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine;
trans-7-cyano-3- (2- (1- (4- (2-thiophenyl) acetamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine;
trans-7-cyano-3- (2- (1- (4- (3-benzothiophenyl) acetamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine;
trans-7-cyano-3- (2- (1- (4- (3- (2- (5-methyl) -1,3,4-oxadiazolyl) benzoyl) amino) cyclohexyl) ethyl) -2,3, 4,5-tetrahydro-1H-3-benzazepine;
trans- (E) -7-Cyano-3- (2- (1- (4- (3- (2-naphthyl) propenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine;
trans-7-Acetyl-3- (2- (1- (4- (3-benzothiophenyl) acetamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine;
trans- (E) -7-Acetyl-3- (2- (1- (4- (3- (4-acetamido) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine;
trans-7-Acetyl-3- (2- (1- (4- (6- (2-amino) benzothiazolyl) acetamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine;
trans-7-Acetyl-3- (2- (1- (4- (8- (1,4-dihydro-4-oxo) quinolinyl) carboxamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro- 1H-3-benzazepine;
trans- (E) -7-Acetyl-3- (2- (1- (4- (3- (2-acetyl) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine;
trans-7-Acetyl-3- (2- (1- (4- (2-benzothiophenyl) acetamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine;
trans- (E) -7-Cyano-3- (2- (1- (4- (3- (5- (3-acetyl) indolyl) propenoyl) amino) cyclohexyl) ethyl) -2,3,4,5 tetrahydro-1H-3-benzazepine;
trans-7-cyano-3- (2- (1- (4- (3- (5- (3-methyl) -1,2,4-oxadiazolyl) benzoyl) amino) cyclohexyl) ethyl) -2,3, 4,5-tetrahydro-1H-3-benzazepine;
trans -7-cyano-3- (2- (1- (4- (5- (2-methyl) benzimidazolyl) acetamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine;
trans-7-cyano-3- (2- (1- (4- (6-quinoxalinyl) acetamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine;
trans- (E) -7-Cyano-3- (2- (1- (4- (3- (3- (2-acetyl) furanyl) propenoyl) amino) cyclohexyl) ethyl) -2,3,4,5 tetrahydro-1H-3-benzazepine;
trans-7-cyano-3- (2- (1- (4- (6- (2-amino) benzoxazolyl) acetamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine;
trans-7-cyano-3- (2- (1- (4- (6- (3,4-dihydro-2-oxo) -2H-benzoxazinyl) acetamido) cyclohexyl) ethyl) -2,3,4,5 tetra tetrahydro-1H-3-benzazepine;
trans- (E) -7-Cyano-3- (2- (1- (4- (3- (2-fluoro-5-acetamido) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5- tetrahydro-1H-3-benzazepine;
trans-7- (5- (3-Methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (2-benzothiophenyl) acetamido) cyclohexyl) ethyl) -2,3,4 , 5-tetrahydro-1H-3-benzazepine;
trans- (E) -7- (5- (3-Methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (3- (3-thienyl) propenoyl) amino) cyclohexyl ) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine;
trans-7- (5- (3-Methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (5-quinolinyl) carboxamido) cyclohexyl) ethyl) -2,3,4 , 5-tetrahydro-1H-3-benzazepine;
trans-7- (5- (3-Methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (3- (3- (5-methyl) -1,2,4 -oxadiazolyl) benzoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine;
trans-7- (5- (3-Methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (8- (1,4-dihydro-4-oxo) quinolinyl) carboxamido ) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine;
trans- (E) -7- (5- (3-Methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (3- (3-fluoro) phenylpropenoyl) amino) cyclohexyl ) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine;
trans- (E) -7- (5- (3-Methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (3- (3-acetamido-2-fluoro) phenylpropenoyl ) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine;
trans- (E) -7- (5- (3-Methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (3- (3-acetyl) phenylpropenoyl) amino) cyclohexyl ) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine;
trans-7- (5- (3-Methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (3-fluoro) phenylacetamido) cyclohexyl) ethyl) -2,3,4 , 5-tetrahydro-1H-3-benzazepine;
trans-7- (5- (3-Methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (2,4-difluoro) phenylacetamido) cyclohexyl) ethyl) -2,3 , 4,5-tetrahydro-1H-3-benzazepine;
trans-7- (5- (3-Methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (2-naphthyl) acetamido) cyclohexyl) ethyl) -2,3,4 , 5-tetrahydro-1H-3-benzazepine;
trans-7- (5- (3-Methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (7- (3,4-dihydro-3-oxo) -2H- benzoxazinyl) carboxamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine;
trans-7- (5- (3-Methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (5- (2-methyl) quinolinyl) carboxamido) cyclohexyl) ethyl) - 2,3,4,5-tetrahydro-1H-3-benzazepine;
trans-7- (5- (3-Methyl) -1,2,4-.oxadiazolyl) -3- (2- (1- (4- (2-fluoro) phenylacetamido) cyclohexyl) ethyl) -2,3, 4,5-tetrahydro-1H-3-benzazepine;
trans-7- (5- (3-Methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (2,5-difluoro) phenylacetamido) cyclohexyl) ethyl) -2,3 , 4,5-tetrahydro-1H-3-benzazepine;
trans-7- (5- (3-Methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (2-indolyl) carboxamido) cyclohexyl) ethyl) -2,3,4 , 5-tetrahydro-1H-3-benzazepine;
trans-7- (3- (5-Methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (2-benzothiophenyl) acetamido) cyclohexyl) ethyl) -2,3,4 , 5-tetrahydro-1H-3-benzazepine;
trans- (E) -7- (3- (5-Methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (3- (3-thienyl) propenoyl) amino) cyclohexyl ) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine;
trans-7- (3- (5-Methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (5-quinolinyl) carboxamido) cyclohexyl) ethyl) -2,3,4 , 5-tetrahydro-1H-3-benzazepine;
trans-7- (3- (5-Methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (3-pyrrolo [2,3-b] pyridyl) carboxamido) cyclohexyl ) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine;
trans-7- (3- (5-Methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (8- (1,4-dihydro-4-oxo) quinolinyl) carboxamido ) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine;
trans-7- (3- (5-Methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (3- (3- (5-methyl) -1,2,4 -oxadiazolyl) benzoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine;
trans- (E) -7- (3- (5-Methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (3- (3-fluoro) phenylpropenoyl) amino) cyclohexyl ) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine;
trans- (E) -7- (3- (5-Methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (3- (2-fluoro) phenylpropenoyl) amino) cyclohexyl ) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine;
trans- (E) -3- (2- (1- (4- (3- (4-fluoro) phenylpropenoyl) amino) cyclohexyl) ethyl) -7-methylsulphonyl-2,3,4,5-tetrahydro-1H- -3-benzazepine;
trans-3- (2- (1- (4- (3- (2- (4-methyl) oxazolyl) benzoyl) amino) cyclohexyl) ethyl) -7-methylsulphonyl-2,3,4,5-tetrahydro-1 H -3-benzazepine;
trans-3- (2- (1- (4- (3-trifluoromethylbenzoyl) amino) cyclohexyl) ethyl) -7-methylsulphonyl-2,3,4,5-tetrahydro-1H-3-benzazepine;
trans-3- (2- (1- (4- (5- (8-chloro-2-methyl) quinolinyl) carboxamido) cyclohexyl) ethyl) -7-methanesulphonyl-2,3,4,5-tetrahydro-1H- -3-benzazepine;
trans-7- (5- (3-Methyl) isoxazolyl) -3- (2- (1- (4- (2-fluoro) phenylacetamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro dro-1H-3-benzazepine;
trans-7- (3- (5-Methyl) isoxazolyl) -3- (2- (1- (4- (4-fluoro) phenylacetamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine;
trans- (E) -7- (2- (5-Methyl) oxazolyl) -3- (2- (1- (4- (3- (4-fluoro) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3 , 4,5-tetrahydro-1H-3-benzazepine;
trans- (E) -7- (3- (5-Methyl) isoxazolyl) -3- (2- (1- (4- (3- (4-fluoro) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3 , 4,5-tetrahydro-1H-3-benzazepine;
trans- (E) -7- (2-Pyridyl) -3- (2- (1- (4- (3- (4-fluoro) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5- tetrahydro-1H-3-benzazepine;
trans- (E) -7- (2-pyrimidyl) -3- (2- (1- (4- (3- (4-fluoro) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5- tetrahydro-1H-3-benzazepine;
trans- (E) -7- (1-pyrrolidinylcarbonyl) -3- (2- (1- (4- (3- (4-fluoro) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5- tetrahydro-1H-3-benzazepine;
trans-7- (1-pyrrolidinylcarbonyl) -3- (2- (1- (4- (3-pyrrolo [2,3-b] pyridyl) carboxamido) cyclohexyl) ethyl) -2,3,4,5- tetrahydro-1H-3-benzazepine;
trans- (E) -7- (5-pyrimidyl) -3- (2- (1- (4- (3- (4-fluoro) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5- tetrahydro-1H-3-benzazepine;
trans-7- (5-pyrimidinyl) -3- (2- (1- (4- (3- (3- (5-methyl) -1,2,4-oxadiazolyl) benzoyl) amino) cyclohexyl) ethyl) - 2,3,4,5-tetrahydro-1H-3-benzazepine;
trans-7- (5-pyrimidinyl) -3- (2- (1- (4- (5- (2-methyl) quinolinyl) carboxamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine;
trans-7- (3- (5-Methyl) isoxazolyl) -3- (2- (1- (4- (5- (2-methyl) quinolinyl) carboxamido) cyclohexyl) ethyl) -2,3,4,5 tetrahydro-1H-3-benzazepine;
trans- (E) -7- (2-Pyridyl) -3- (2- (1- (4- (3- (2-cyano) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5- tetrahydro-1H-3-benzazepine;
trans- (E) -7- (2-Pyridyl) -3- (2- (1- (4- (3- (3-cyano) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5- tetrahydro-1H-3-benzazepine;
trans- (E) -7- (2-Pyridyl) -3- (2- (1- (4- (3- (4-cyano) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5- tetrahydro-1H-3-benzazepine;
trans-3- (2- (1- (4- (5- (8-fluoro-2-methyl) quinolinyl) carboxamido) cyclohexyl) ethyl) -7-methylsulphonyl-2,3,4,5-tetrahydro-1H- -3-benzazepine;
trans-3- (2- (1- (4- (5- (8-fluoro-2-methyl) quinolinyl) carboxamido) cyclohexyl) ethyl) -7-methylsulfonyloxy-2,3,4,5-tetrahydro-1H- -3-benzazepine;
trans-3- (2- (1- (4- (3- (2- (5-Methyl) oxazolyl) benzoyl) amino) cyclohexyl) ethyl) -7-methylsulfonyloxy-2,3,4,5-tetrahydro-1 H -3-benzazepine.

These Connections can in the form of their free base or as physiologically acceptable salts thereof are present, in particular the monohydrochloride or Monomesylatsalzen.

• (a) Umsetzen einer Verbindung der Formel (II):
  
  Formel (II) wobei R¹, R² und q wie vorstehend definiert sind, mit einer Verbindung der Formel (III): A-COX

The present invention also provides a process for the preparation of compounds of formula (I), comprising:

• (a) reacting a compound of formula (II):
  
  Formula (II) wherein R ¹ , R ² and q are as defined above, with a compound of formula (III): A-COX

Formula (III)

• where A is as defined above and X a halogen atom or the residue of an activated ester;
• (b) to produce a compound of formula (I), reacting a compound of formula (II) with a compound A-Br or Al or A-OSO ₂ CF ₃ in the presence of carbon monoxide and a catalyst such as trans-bis-triphenylphosphine palladium bromide (II);
• (c) to produce a compound of formula (I) wherein R ^{1 is} Ar ³ -Z and Z is a bond, reacting a compound of formula (IV):
  
  Formula (IV) wherein R ² and A are as defined above, a radical R ^{1a is} a radical W, wherein W is a halogen atom or a Trifluormethylsulfonyloxyrest, or W is a radical M selected from a Borderivat, for example a boric acid function B (OH eg SnBu, and when q is 2, the other R ^1a) _2, or a metal function such as trialkylstannyl _3, zinc halide or magnesium halide is equal to R ^1; with a compound Ar ³ -W ¹ , wherein W ^{1 is} a halogen atom or a trifluoromethylsulfonyloxy when W is M or W ^{1 is} M when W is halogen or trifluoromethylsulfonyloxy;
• (d) to produce a compound of formula (I) wherein R ^{1 is} Ar ³ -Z and Z is O or S, reacting a compound of formula (V):
  
  Formula (V) wherein R ² and A are as defined above, one R ^{1b is} ZH and when q is 2 the other R ^1b is R ¹ ; with a reagent for introducing the residue Ar ³ ;
• (e) to produce a compound of formula (I) wherein Y is a bond, reacting a compound of formula (VI):
  
  Formula (VI) wherein R ¹ , R ² , Ar ¹ , W and q are as defined above, with a compound Ar ² -W ¹ , wherein W ^{1 is} a halogen atom or a trifluoromethylsulfonyloxy when W is M or W ^{1 is} a group M when W is a halogen atom or a trifluoromethylsulfonyloxy group;
• (f) converting a compound of formula (I) into another compound of formula (I) by, for example, (i) alkylating a compound (I) wherein R ^{2 is} hydrogen, (ii) converting a residue R ¹ from alkoxy (eg Methoxy) in hydroxy, or (iii) converting the radical R ¹ from hydroxy to sulphonyloxy, eg, alkylsulfonyloxy or trifluoromethanesulfonyloxy, (iv) converting a compound in which Y is S into a compound wherein Y is SO ₂ , or (v) converting Y from CO to CH ₂ ;
• (g) separating cis and trans isomers of the compounds of formula (I) by conventional methods, eg chromatography or crystallization; and optionally subsequently forming a salt of formula (I).

The Method (a) can be carried out be by conventional A method for forming an amide bond can be used. If X the residue is an activated ester, this may be e.g. with one Carbodiimide, such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide become. The reaction may be carried out in a solvent such as dichloromethane carried out become.

The reaction of a compound of the formula (IV) with Ar ³ W ¹ by process (c) or a compound of the formula (VI) with Ar ² -W ¹ by process (e) can be carried out in the presence of a transition metal, for example a palladium catalyst, such as bis-triphenylphosphine palladium dichloride or tetrakis triphenylphosphine palladium (0). When M is a boric acid function such as B (OH) ₂ , the reaction may be carried out under basic conditions, for example using aqueous sodium carbonate in a suitable solvent such as dioxane. When M is a trialkyltin residue, the reaction may be carried out in an inert solvent such as xylene or dioxane, optionally in the presence of LiCl. When M is a zinc or magnesium halide, the reaction can be carried out in an aprotic solvent such as tetrahydrofuran. The substituent W is preferably a halogen atom such as bromine or a sulfonyloxy group such as the trifluoromethylsulfonyloxy group; and W ¹ is preferably a group M such as a trialkyltin residue or B (OH) ₂ .

In the method (d) the reagent serving to introduce the group Ar ^3, preferably a compound of formula Ar ³ -Hal, wherein Hal represents a halogen atom. The reaction may be carried out in the presence of a base such as potassium carbonate in a solvent such as dimethylformamide.

The transfer reactions according to the method (f) can using techniques well known in the art.

Formel (VII) in ein entsprechendes Keton, gefolgt von einer reduktiven Aminierung hergestellt werden. Dies kann nach im Fachgebiet weithin bekannten Verfahren für (i) Überführung eines Ketals in ein Keton in Gegenwart von wässriger Säure; gefolgt von (ii) reduktiver Aminierung des Ketons mit R²NH₂ oder Ammoniumacetat in Gegenwart eines Reduktionsmittels ausgeführt werden. Geeignete Reduktionsmittel, die verwendet werden können, schließen Natriumborhydrid, Cyanoborhydrid oder Triacetoxyborhydrid unter sauren Bedingungen oder katalytische Hydrierung ein. Die Umsetzung kann günstigerweise in einem Lösungsmittel, wie Methanol, Ethanol oder Dichlorethan, ausgeführt werden.The compounds of the formula (II) can be prepared by conversion of a compound of the formula (VII) in which R ¹ and q are as defined above,

Formula (VII) can be prepared in a corresponding ketone, followed by a reductive amination. This can be done by methods well known in the art for (i) converting a ketal to a ketone in the presence of aqueous acid; followed by (ii) reductive amination of the ketone with R ² NH ₂ or ammonium acetate in the presence of a reducing agent. Suitable reducing agents which may be used include sodium borohydride, cyanoborohydride or triacetoxyborohydride under acidic conditions or catalytic hydrogenation. The reaction may conveniently be carried out in a solvent such as methanol, ethanol or dichloroethane.

Formel (VIII) in der R¹ und q wie vorstehend definiert sind; mit einer Verbindung der Formel (IX)

Formel (IX) in Gegenwart eines Reduktionsmittels umgesetzt wird. Geeignete Reduktionsmittel, die verwendet werden können, schließen Natriumborhydrid, Cyanoborhydrid oder Triacetoxyborhydrid unter sauren Bedingungen oder katalytische Hydrierung ein. Die Umsetzung kann günstigerweise in einem Lösungsmittel, wie Ethanol oder Dichlorethan, ausgeführt werden.A compound of formula (VII) itself may be prepared by reacting a compound of formula (VIII)

Formula (VIII) wherein R ¹ and q are as defined above; with a compound of the formula (IX)

Formula (IX) is reacted in the presence of a reducing agent. Suitable reducing agents which may be used include sodium borohydride, cyanoborohydride or triacetoxyborohydride under acidic conditions or catalytic hydrogenation. The reaction may conveniently be carried out in a solvent such as ethanol or dichloroethane.

Formel (X) wobei R² wie vorstehend definiert ist und P eine Schutzgruppe darstellt, zum Beispiel eine Trifluoracetyl- oder tert-Butoxycarbonylgruppe. Die anschließende Umsetzung einer Verbindung der Formel (X) mit einer Verbindung der Formel (VIII) in Gegenwart eines Reduktionsmittels, wie es vorstehend beschrieben ist, gefolgt von der Entfernung der Schutzgruppe unter Verwendung von Standardmethoden, ergibt die einzelnen Isomere einer Verbindung der Formel (II), in der R² wie vorstehend definiert ist.The individual cis and trans isomers of a compound of formula (II) can be prepared by starting from cis- or trans-4-aminocyclohexaneacetic acid (TP Johnson, et al., J.Med.Chem., 1997, (20 ), 279-290), followed by replacement of the functional groups and / or protecting by methods well known in the art to obtain the individual cis and trans isomers of a compound of formula (X)

Formula (X) wherein R ^{2 is} as defined above and P is a protecting group, for example a trifluoroacetyl or tert-butoxycarbonyl group. Subsequent reaction of a compound of formula (X) with a compound of formula (VIII) in the presence of a reducing agent as described above followed by removal of the protecting group using standard methods yields the individual isomers of a compound of formula (II ) in which R ^{2 is} as defined above.

links of the formula (III) are known or can be prepared using standard methods become.

Compounds of formula (IV), (V) or (VI) may be prepared by methods analogous to methods (a), (b), (c) and (d) described above. The compounds Ar ² W ¹ , Ar ³ W ¹ and Ar ³ Hal are available in Hundel or can be prepared by standard methods. Compounds of the formula (VIII) in which R ^{1 represents} a halogen atom, a methoxy, acetyl, cyano, carboxylic acid or carboxamide group are known in the literature or can be prepared by known methods. The compound of the formula (IX) is likewise known in the literature.

Formel (XI) The conversion of a compound of the formula (VIII) in which R ^{1 represents} a cyano or acetyl group into a compound of the formula (VIII) in which R ^{1 represents} an Ar ³ Z radical, where Ar represents an oxadiazole or an isoxazole ring and Z is a bond can be carried out by (i) converting a compound of formula (XI) wherein R ¹ and q are as defined above using standard methods; (ii) converting R ¹ from a cyano group to an oxadiazolyl group using known methods or converting an acetyl group to an isoxazolyl group using known methods; (iii) removing the protecting group of a compound of formula (XI) to a compound of formula (VIII) using standard methods.

Formula (XI)

It has been found that the compounds of formula (I) have an affinity for dopamine receptors, especially for the D ₃ receptor, and are expected to be useful for the treatment of disease conditions that require the modulation of such receptors, such as psychotic states. It has also been found that the compounds of formula (I) have a greater affinity for dopamine D ₃ receptors than for D ₂ receptors. It is believed that the therapeutic effect of currently available antipsychotic agents (neuroleptics) is exerted via blockade of D ₂ receptors; however, this mechanism is also believed to be responsible for undesirable extrapyramidal side effects (eps) associated with many neuroleptic agents. Wishing to be unauthentic, it has been proposed that the blockade of the recently characterized dopamine D ₃ receptor could give rise to beneficial antipsychotic effects without substantial eps. (See, for example, Sokoloff et al., Nature, 1990; 347: 146-151; and Schwartz et al., Clinical Neuropharmacology, Vol. 16, No. 4, 295-314, 1993). Preferred compounds of this invention are therefore those which have a higher affinity for dopamine D ₃ than for dopamine D ₂ receptors (such affinity can be measured using standard methodology, for example the use of cloned dopamine receptors). Such compounds can be advantageously used as selective modulators of the D ₃ receptors.

The compounds of formula (I) are of potential use as antipsychotic agents, for example in the treatment of schizophrenia, schizo-affective disorders, psychotic depression, mania, paranoid and delusional disorders. Furthermore, they may be useful as adjunctive therapy in Parkinson's disease, particularly with compounds such as L-DOPA and possibly dopaminergic agonists, to reduce the side effects experienced by these long-term treatments (see, eg, Schwartz et al., Brain Res Reviews, 1998, 26, 236-242). Because of the localization of D ₃ receptors, it may also be envisaged that the compounds could be of use in the treatment of the abuse of substances believed to involve D ₃ receptors (see, eg, Levant, 1997, Pharmacol., Rev., 49, 231-252). Examples of such substance abuse include alcohol, cocaine and nicotine abuse. Other conditions that can be treated by the compounds include dyskinetic disorders such as Parkinson's disease, neurolepsy-induced Parkinsonism, and tardive dyskinesias; Depression; Anxiety, cognitive impairment, including memory disorders such as Alzheimer's disease, eating disorders, sexual dysfunctions, sleep disorders, vomiting, movement disorders, obsessive-compulsive disorder, amnesia, aggression, autism, dizziness, dementia, circadian rhythm disorders, and disorders of gastric motility, eg, IBS; one.

In a further aspect, therefore, the present invention provides a method of treating conditions requiring modulation of dopamine D ₃ receptors, for example psychoses, such as schizophrenia, comprising administering an effective amount of a compound of formula (I) or a physiologically acceptable salt thereof to a patient in need thereof.

The invention also provides the use of a compound of formula (I) or a physiologically acceptable salt thereof for the manufacture of a medicament for the treatment of conditions requiring modulation of dopamine D ₃ receptors, for example psychoses such as schizophrenia.

A preferred use for D ₃ antagonists according to the present invention is the treatment of psychoses, such as schizophrenia.

For the use in medicine, the compounds of the invention are normally administered as a standard drug. The present invention Therefore, in another embodiment, provides drugs, comprising a novel compound of the formula (I) or a physiological compatible Salt thereof and a physiologically acceptable carrier.

The Compounds of formula (I) can by any cheap Be administered by, for example, oral, parenteral, buccal, sublingual, nasal, rectal or transdermal administration and the medicines can be adjusted accordingly.

The Compounds of formula (I) and their physiologically acceptable Salts that are effective when given orally can be considered as liquids or solids, for example as syrups, suspensions or emulsions, tablets, capsules and pills.

A liquid formulation will generally consist of a suspension or solution of the compound or physiologically acceptable salt in a suitable liquid carrier (s), for example, an aqueous solvent such as water, ethanol or glycerine, or a non-aqueous solution medium, such as polyethylene glycol or an oil. The formulation may also contain a suspending agent, preservative, flavoring or coloring agent.

A Composition in the form of a tablet can be prepared by any suitable pharmaceutical carrier routinely used for Preparation of solid formulations is used becomes. Examples of such carriers shut down Magnesium stearate, starch, Lactose, sucrose and cellulose.

A Composition in the form of a capsule can be made by using routine encapsulation procedures. For example For example, a granule containing the active ingredient may be prepared using standard carriers and then stuffed into a hard gelatin capsule; in another embodiment may be a dispersion or suspension using each suitable pharmaceutical carrier, for example, aqueous Gums, celluloses, silicates or oils, are manufactured and The dispersion or suspension can then be transformed into a soft gelatin capsule filled become.

typical Parenteral compositions consist of a solution or Suspension of the compound or a physiologically acceptable Salt in a sterile aqueous Carrier or a physiologically acceptable oil, for example Polyethylene glycol, polyvinylpyrrolidone, lecithin, peanut oil or sesame oil. In a another embodiment can the solution be lyophilized and then with a suitable solvent reconstituted immediately before administration.

compositions for the nasal administration favorably be formulated as aerosols, drops, gels and powders. aerosol formulations typically include a solution or a fine suspension of the active substance in a physiological acceptable aqueous or non-aqueous solvent and are usually given in single or multiple doses sterile form presented in a sealed container in the form a cartridge or replacement cartridge for use with a nebulizer can. In another embodiment can the sealed container a uniform dispersion device, such as a single-dose nasal inhaler or an aerosol dispenser equipped with a metering valve, which is intended for disposal when the contents of the container is consumed have been. When the dosage forms comprise an aerosol dispenser, this will contain a propellant that is a compressed one Gas, such as compressed air, or an organic propellant, as a chlorofluorocarbon can act. The aerosol dosage forms can also the shape of a pump sprayer taking.

compositions the for a buccal or sublingual administration are suitable, include tablets, Pills and lozenges one in which the active ingredient with a carrier, sugar and gum arabic, tragacanth or gelatin and glycerin is.

compositions for the Rectal administration is conveniently in the form of suppositories, the one conventional Suppository base, like cocoa butter, included.

compositions the for suitable for transdermal administration include ointments, Gels and patches.

Preferably the composition is in a unit dosage form such as a tablet, capsule or ampoule.

each Dosage form for containing oral administration preferably from 1 to 250 mg (and for parenteral administration contains from 0.1 to 25 mg) of a compound of the formula (I) or a physiologically compatible Salt thereof, calculated as the free base.

The according to the invention, physiologically acceptable Compounds are usually given after a daily dosage regimen (for an adult Person) of, for example, an oral dose between 1 mg and 500 mg, preferably between 10 mg and 400 mg, e.g. between 10 mg and 250 mg, or an intravenous, subcutaneous or intramuscular Dose between 0.1 and 100 mg, preferably between 0.1 mg and 50 mg, e.g. between 1 mg and 25 mg of the compound of the formula (I) or a physiologically acceptable one Salt thereof, calculated as the free base, administered, the Compound is administered 1 to 4 times a day. suitably will the connections for administered the period of continuous therapy, for example for one Week or more.

Biological test procedures

The ability of the compounds to bind selectively to human D ₃ dopamine receptors can be demonstrated by measuring their binding to cloned receptors. The inhibition constants (K _i ) of the test compounds for the displacement of [ ¹²⁵ I] iodosulpride bound to human D ₃ dopamine receptors expressed in CHO cells was determined as follows. The cell lines were shown to be free of bacterial, fungal and mycoplasmic contaminants and the stock solutions of each were stored in liquid nitrogen. The cultures were grown as a molecular film or in suspension in standard cell culture media. The cells were recovered by scraping (from the molecular film) or by centrifugation (from suspension cultures), and were washed two or three times by suspension in phosphate-free buffered saline, followed by collection by centrifugation. The cell granules were stored frozen at -40 ° C. Crude cell membranes were prepared by homogenization followed by high speed centrifugation and characterization of cloned receptors was achieved by binding radioligands.

Production of CHO Cell Membranes

cell granules was gently thawed at room temperature and again in about 20 Volumes of ice cold 50 mM Tris salts (pH 7.4 @ 37 ° C), 20 mM EDTA, 0.2 M sucrose suspended. The suspension was used Ultra-Turrax homogenized at full speed for 15 sec. The homogenate was incubated at 18,000 rpm for 20 min. At 4 ° C Sorvall RC5C centrifuge centrifuged. The membrane granules were in ice-cold 50 mM Tris salts (pH 7.4 @ 37 ° C) using an Ultra-Turrax resuspended, and again at 18,000 rpm for 20 min. at 4 ° C in one Sorvall RC5C centrifuge centrifuged. The membranes were still washed twice with 50 mM Trissalzen (pH 7.4 @ 37 ° C). The final granulate was resuspended in 50 mM Tris salts (pH 7.4 @ 37 ° C) and the protein content was determined using bovine albumin as a standard. (Bradford, M.M. (1976) Anal Biochem., 72, 248-254).

Binding experiments on cloned dopamine receptors

Crude cell membranes were incubated with 0.1 nM [ ¹²⁵ I] -odosulpride (~2000 Ci / mmol, Amersham, UK) and the test compound was dissolved in a buffer containing 50 mM Tris salts (pH 7.4 @ 37 ° C.), 120 mM NaCl, 5 mM KCl, 2 mM CaCl ₂ , 1 mM MgCl ₂ , 0.1% (w / v) bovine serum albumin, in a total volume of 1 ml for 30 min. at 37 ° C. After incubation, the samples were filtered using a Brundel Cell Harvester and washed three times with ice-cold 50 mM Tris Salts (pH 7.4 @ 37 ° C.), 120 mM NaCl, 5 mM KCl, 2 mM CaCl ₂ and 1 mM MgCl ₂ , The radioactivity on the filters was measured using a Cobra gamma counter (Canberra Packard). Non-specific binding was defined as the binding of radioligands which remains after incubation in the presence of 100 μM iodosulpride. For comparative curves, 14 concentrations (semi-log dilutions) of competing cold drug were used. The comparison curves were analyzed simultaneously using, whenever possible, nonlinear least squares fit procedures suitable for fitting to models for one, two or three reaction sites.

Compounds of the examples tested by this method had pKi values in the range of 7.0-9.0 at the cloned human D ₃ receptor.

Functional effect cloned dopamine receptors

The functional effect of compounds on human D2 and human D3 receptors (ie agonism or antagonism) can be determined using a cytosensor microphysiometer (McConnell HM et al., Science 1992, 257, 1906-1912). In microphysiometer experiments, cells (hD2_CHO or hD3_CHO) at a concentration of 300,000 cells / dish are inoculated into fetal calf (FCS) serum in 12 mm Transwell inserts. The cells were incubated for 6 hours at 37 ° C in 5% CO ₂ before switching to an FCS-free medium. After a further 16-18 hours, the cups were placed in the sensor chambers of the Cytosensor Microphysiometer (Molecular Devices) and the chambers were filled with flow medium (bicarbonate-free Dulbecco's modified Eagles medium containing 2 mM glutamine and 44 mM NaCl) at a flow rate of 10 perfused μl / minute. Each pumping cycle lasted 90 s. The pump was on for the first 60 seconds and the acidification rate was determined to be between 68 and 88 seconds using the Cytosoft program. The test compounds were diluted in the flow medium. In the experiments to determine the effect as agonist, the cells were exposed to growing concentrations of a putative agonist at half-hour intervals (4.5 min for hD2, 7.5 min for hD3). They became them ben concentrations of the suspected agonist used. The peak of the acidification rate for each concentration of the putative agonist was determined and the concentration-response curve adjusted using Robofit [Tilford, NS, Bowen, WP & Baxter, GS, Br. J. Pharmacol. (1995) in press]. In experiments to determine efficacy as antagonists, cells were treated at 30 min intervals with five pulses of a submaximal concentration of quinpirol (100 nM for hD2 cells, 30 nM for hD3 cells) before being exposed to the lowest concentration of the putative antagonist were. At the end of the next 30 min interval, the cells were again exposed to a quinpirole pulse (with the antagonist persistent) before being exposed to the next higher concentration of the antagonist. In total, 5 concentrations of the antagonist were used in each experiment. The peak of the acidification rate at each agonist concentration was determined and the concentration-inhibition curves were adjusted using Robofit.

The compounds of the examples tested by this method were shown to be antagonists with pKb values in the range of 7.0-10.0 at the cloned human D ₃ receptor.

pharmaceutical formulations

• Puffer: Mögliche Puffer schließen Citrat, Phosphat, Natriumhydroxid/Chlorwasserstoffsäure ein.
• Lösungsmittel: Typischerweise Wasser, jedoch können auch Cyclodextrine (1-100 mg) und Co-Lösungsmittel, wie Propylenglykol, Polyethylenglykol und Alkohol eingeschlossen sein.

Tablette Verbindung 1-40 mg Verdünnungsmitte/Füllstoff * 50-250 mg Bindemittel 5-25 mg Sprengmittel 5-50 mg Gleitmittel 1-5 mg Cyclodextrin 1-100 mg Verdünnungsmittel: z.B. microkristalline Cellulose, Lactose, Stärke Bindemittel: z.B. Polyvinylpyrrolidon, Hydroxypropylmethyl-cellulose Sprengmittel: z.B. Natrium-Stärke-Glycollat, Crospovidon Gleitmittel: z.B. Magnesiumstearat, Natriumstearylfumarat. Orale Suspension Verbindung 1-40 mg Suspensionsmittel 0,1-10 mg Verdünnungsmttel 20-60 mg Konservierungsmittel 0,01-1,0 mg Puffer auf pH ca. 5-8 Co-Lösungsmittel 0-40 mg Geschmacksstoff 0,01-1,0 mg Färbemittel 0,001-0,1 mg Suspensionsmittel: z.B. Xanthangummi, mikrokristalline Cellulose Verdünnungsmittel : z.B. Sorbitollösung, typischerweise Wasser Konservierungsmittel: z.B. Natriumbenzoat Puffer: z.B. Citrat Co-Lösungsmittel: z.B. Alcohol, Propylenglykol, Polyethylenglykol, Cyclodextrin The following is a description of typical pharmaceutical formulations according to the present invention which can be prepared using standard procedures. IV infusion Compound of the formula (I) 1-40 mg buffer to pH about 7 Solvent / complexing agent to 100 ml Bolus injection Compound of the formula (I) 1-40 mg buffer to pH about 7 Cosolvent to 5 ml

• Buffer: Possible buffers include citrate, phosphate, sodium hydroxide / hydrochloric acid.
• Solvent: Typically water, but cyclodextrins (1-100 mg) and cosolvents such as propylene glycol, polyethylene glycol and alcohol may also be included.

tablet connection 1-40 mg Diluent / filler * 50-250 mg binder 5-25 mg explosives 5-50 mg lubricant 1-5 mg cyclodextrin 1-100 mg Thinner: eg microcrystalline cellulose, lactose, starch Binder: for example, polyvinylpyrrolidone, hydroxypropylmethyl-cellulose Disintegrants: eg sodium starch glycollate, crospovidone Lubricant: eg magnesium stearate, sodium stearyl fumarate. Oral suspension connection 1-40 mg suspending agent 0.1-10 mg Verdünnungsmttel 20-60 mg preservative 0.01-1.0 mg buffer to pH about 5-8 Cosolvent 0-40 mg flavoring 0.01-1.0 mg dye 0.001-0.1 mg Suspending agents: eg xanthan gum, microcrystalline cellulose Diluent: eg sorbitol solution, typically water Preservatives: eg sodium benzoate Buffer: eg citrate Co-Solvent: eg alcohol, propylene glycol, polyethylene glycol, cyclodextrin

The Invention is further characterized by the following non-limiting Example illustrates:

Description 1

2,3,4,5-tetrahydro-1H-3-benzazepine

1,2-Phenylenediacetonitrile (7.5 g, 48 mmol) dissolved in ethanol (150 ml) was added to Raney Ni (2 g), which was previously washed with ethanol (3 × 20 ml). The mixture was then hydrogenated at 50 ° C and a pressure of 50 psi with shaking for 24 hours. The reaction mixture was then cooled to room temperature and filtered through a plug of diatomaceous earth and washed thoroughly with ethanol (100 ml). The filtrate was evaporated in vacuo to give a brown oil which was chromatographed over silica gel (100 g) eluting with 2-10% methanol in CH ₂ Cl _{2 to give} the title compound as a brown oil (2.45 g, 35%).
Mass Spectrum (API ⁺ ) Found: 148 (MH ⁺ ). C ₁₀ H ₁₃ N requires 147.

Description 2

trans-3- (2- (1- (4- (N-tert-butoxycarbonyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine

Sodium triacetoxyborohydride (4.3 g, 20.4 mmol) was added to a mixture of 2,3,4,5-tetrahydro-1H-3-benzazepine (2.0 g, 13.6 mmol) and trans-2- (1 - (4- (N-tert-Butoxycarbonyl) amino) cyclohexyl) acetaldehyde in 1,2-dichloroethane (200 ml) and the mixture was stirred at room temperature for 0.5 h. The reaction mixture was diluted with CH ₂ Cl ₂ (100 mL) and washed with saturated aqueous K ₂ CO ₃ solution (200 mL), followed by brine (100 mL). The organic layer was separated and dried over Na ₂ SO ₄ and then evaporated in vacuo to give an off-white solid which was chromatographed on silica gel eluting with ethyl acetate to give the title compound as an off-white solid (3.13g) g, 62%).
Mass spectrum (API ⁺ ): Found 373. C ₂₃ H ₃₆ N ₂ O ₂ requires 372.

The The following compounds were prepared in a similar manner as in description 2.

(a) trans-3- (2- (1- (4-N-tert-butoxycarbonyl) amino) cyclohexyl) ethyl-6-methoxy-2,3,4,5-tetrahydro-1H-3-benzazapine

• Mass spectrum (API ⁺ ): Found 403 (MH ⁺ ). C ₂₄ H ₃₈ N ₂ O ₃ requires 402nd

(b) trans-3- (2- (1- (4-N-tert-butyloxycarbonyl) amino) cyclohexyl) ethyl-7-cyano-2,3,4,5-tetrahydro-1H-3-benzazepine

• Mass spectrum (API ⁺ ) Found 398 (MH ⁺ ). C ₂₄ H ₃₅ N ₃ O ₂ requires 397th
• ¹ H NMR (CDCl ₃ ) δ: 0.97-1.13 (4H, m), 1.22 (1H, m), 1.36-1.47 (11H, m), 1.71-1, 79 (2H, m), 1.95-2.04 (2H, m), 2.48 (2H, m), 2.61 (4H, m), 2.90-3.00 (4H, m) , 3.37 (1H, m), 4.35 (1H, m), 7.17 (1H, d, J = 5 Hz), 7.36 (1H, s), 7.52 (1H, d, J = 5 Hz).

Description 3

trans-3- (2- (1- (4-Amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine

A mixture of trans -2- (2- (1- (4- (N-tert-butoxycarbonyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine (3.1 g , 8.3 mmol) and trifluoroacetic acid (5 ml) in CH ₂ Cl ₂ (50 ml) was stirred at room temperature for 1 h and then at 40 ° C for 1 h. The reaction mixture was then diluted with CH ₂ Cl ₂ (100 mL) and washed with saturated aqueous and K ₂ CO ₃ solution (2 x 100 mL). The organic layer was dried over Na ₂ SO ₄ and then evaporated under vacuum to give the title compound as a brown oil (2.14 g, 95%).
Mass spectrum (API ⁺ ): Found 273 (MH ⁺ ). C ₁₈ H ₂₈ N ₂ requires 272.

The The following compound was prepared in a similar manner as in description 3.

(a) trans-3- (2- (1- (4-amino) cyclohexyl) ethyl) -6-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

• Mass spectrum (API ⁺ ): Found 303 (MH ⁺ ). C ₁₉ H ₃₀ N ₂ O requires 302.

b) trans-3- (2- (1- (4-amino) cyclohexyl) ethyl) -7-cyano-2,3,4,5-tetrahydro-1H-3-benzazepine

• Mass spectrum (API ⁺ ): Found 298 (MH ⁺ ). C ₁₉ H ₂₇ N ₃ requires 297.
• ¹ H NMR _(CDCl3) δ: 0.92 to 1.18 (6H, m), 1.21 (1H, m), 1.41 (2H, m), 1.75 (2H, m), 1 , 85 (2H, m), 2.49 (2H, m), 2.60 (5H, m), 2.95 (4H, m), 7.16 (1H, d, J = 5 Hz), 7 , 36 (1H, s), 7.40 (1H, d, J = 5 Hz).

Description 4

trans-2- (1- (4- (N-tert-butyloxycarbonyl) amino) cyclohexyl) methyl acetate

A mixture of trans- (4-amino) cyclohexylacetic acid bisulfate (TP Johnston et al., J. Med. Chem., 1977, 20 (2), 279-290), (27.0 g, 106 mmol), conc , H ₂ SO ₄ (3 mL) and methanol (300 mL) was stirred at reflux for 5 h. The resulting solution was filtered and the filtrate evaporated under vacuum to give a brown oil (36 g). A mixture of this material, triethylamine (36 mL, 26.1 g, 259 mmol), dichloromethane (600 mL) and di-t-butyl dicarbonate (25.5 g, 117 mmol) was stirred at 20 ° C for 18 h. The resulting solution was partitioned between saturated aqueous NaHCO ₃ (500 ml) and dichloromethane (3 × 200 ml), the combined extracts were dried (Na ₂ SO ₄ ) and evaporated in vacuo to give the title compound as a colorless solid (24 , 6 g, 86%).
¹ H NMR _(CDCl3) δ: 1.08 (4H, m), 1.43 (9H, s), 1.76 (3H, m), 2.00 (2H, m), 2.20 (2H , d, J = 7 Hz), 3.37 (1H, m), 3.66 (3H, s), 4.39 (1H, br s).

Description 5

trans-2- (1- (4- (N-tert-butyloxycarbonyl) amino) cyclohexyl) acetaldehyde

To a stirred solution of trans-2- (1- (4- (N-tert-butyloxycarbonyl) amino) cyclohexyl) acetic acid methyl ester (46.0 g, 170 mmol) in dry toluene (920 mL) at -78 ° C was added Argon dropwise added a solution of diisobutylaluminum hydride (1 M, 285 mL, 285 mmol) over 0.5 h. The resulting solution was stirred for a further 0.3 h and quenched with a mixture of methanol (28 mL) in toluene (50 mL) and then poured into a saturated aqueous potassium sodium tartrate solution (1.2 L). The resulting mixture was extracted with ether (4 x 1 L). the combined organic extracts were dried (Na ₂ SO ₄ ) and evaporated in vacuo to give a waxy solid which was purified using silica gel eluted with 10-50% ethyl acetate / hexane to give the title compound as a colorless solid was (21.77 g, 53%).
¹ H NMR _(CDCl3) δ: 1.12 (4H, m), 1.44 (9H, s), 1.78 (3H, m), 2.00 (2H, m), 2.33 (2H , dd, J = 7, 2 Hz), 3.37 (1H, m), 4.40 (1H, m), 9.75 (1H, m).

Description 6

7-hydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide

7-Methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (10 g) in 48% aqueous hydrobromic acid (350 ml) was stirred at 100 ° C for 4 h. The mixture was cooled to 20 ° C and then evaporated to dryness under vacuum to give the title compound as a brown solid.
Mass spectrum (API ⁺ ): Found 164 (MH ⁺ ). C ₁₀ H ₁₃ NO requires 163.
¹ H NMR (DMSO) δ: 2.80-3.25 (8H, m), 4.42 (2H, br s), 6.50-6.70 (2H, m), 6.98 (1H, d, J = 8 Hz), 8.86 (1H, brs).

Description 7

3- (tert-butyloxycarbonyl) -7-hydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine

To a solution of 7-hydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (14.5 g) in tetrahydrofuran (100 ml) and water (70 ml) was added triethylamine (8 g) followed by a solution of di-tert-butyl dicarbonate (14 g) in THF (20 ml). The resulting mixture was stirred at 20 ° C for 16 h and partitioned between ethyl acetate (200 mL) and water (200 mL). The aqueous layer was washed with ethyl acetate (100 ml). The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution (100 ml), dried (Na ₂ SO ₄ ) and evaporated to dryness in vacuo. The resulting oil was purified by silica gel chromatography. Elution with ethyl acetate in hexane (10% -30%) gave the title compound (8 g).
Mass spectrum (API ⁺ ): Found 164 (MH ⁺ -Boc). C ₁₅ H ₂₁ NO ₃ requires 263.
¹ H NMR (CDCl ₃ ) δ: 1.48 (9H, s), 2.75-2.87 (4H, m), 3.40-3.60 (4H, m), 4.95 (1H, s), 6.50-6.62 (2H, m), 6.96 (1H, d, J = 8 Hz).

Description 8

3- (tert-butyloxycarbonyl) -7-trifluoromethylsulfonyloxy-2,3,4,5-tetrahydro-1H-3-benzazepine

To a stirred mixture of 3- (tert-butyloxycarbonyl) -7-hydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine (7 g) and triethylamine (5.4 ml) in dry dichloromethane was added 20 ° C under argon added dropwise trifluoromethanesulfonic anhydride (5 ml). The resulting mixture was allowed to warm slowly to 20 ° C over 16 h, then poured into saturated aqueous sodium bicarbonate solution (200 mL) and extracted with dichloromethane (2 x 150 mL). The combined organic extracts were washed with brine (150 ml), dried (Na ₂ SO ₄ ) and evaporated in vacuo to give an amber oil. Silica gel chromatography eluting with ethyl acetate in hexane (10% -30%) gave the title compound (7g) as an amber oil.
Mass spectrum (API ⁺ ): Found 396 (MH ⁺ ). C ₁₆ H ₂₀ F ₃ NO ₅ S requires 395.
¹ H NMR _(CDCl3) δ: 1.48 (9H, s), 2.85-2.95 (4H, m), 3.5-3.65 (4H, m), 7.00 to 7, 05 (2H, m), 7.15-7.27 (1H, m).

Description 9

3- (tert-butyloxycarbonyl) -7-cyano-2,3,4,5-tetrahydro-1H-3-benzazepine

A mixture of 3- (tert-butoxycarbonyl) -7-trifluoromethylsulfonyloxy-2,3,4,5-tetrahydro-1H-3-benzazepine (4.78 g, 12.1 mmol), zinc cyanide (1.42 g, 15 , 6 mmol) and tetrakis-triphenylphosphine-palladium (0) (1.4 g, 1.2 mmol, 10 mol%) in dry dimethylformamide (50 ml) was stirred under argon at 100 ° C for 3 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (120 ml) and filtered. The filtrate was washed with saturated aqueous sodium bicarbonate solution (100 ml), then with water (2 × 50 ml) and then brine (50 ml). The organic layer was dried over sodium sulfate and evaporated in vacuo to give a brown oil, which was purified by chromatography on silica gel eluting with 20-100% ethyl acetate-hexane to give the title compound as a brown oil (0.765 g). 23%).
Mass spectrum (API ⁺ ): Found 173 (MH ⁺ -Boc). C ₁₆ H ₂₀ N ₂ O ₂ requires 272.
¹ H NMR _(CDCl3) δ: 1.47 (9H, s), 2.93 (4H, m), 3.56 (4H, m), 7.21 (1H, d, J = 8 Hz), 7.42 (2H, m).

Description 10

7-Cyano-2,3,4,5-tetrahydro-1H-3-benzazepine

A mixture of 3- (tert-butoxycarbonyl) -7-cyano-2,3,4,5-tetrahydro-1H-3-benzazepine (765mg, 2.81mmol) and trifluoroacetic acid (2mL) in dichloromethane (20mL The reaction mixture was evaporated to dryness under vacuum and partitioned between ethyl acetate (50 ml) and water (50 ml). The aqueous layer was basified using potassium carbonate and extracted again with ethyl acetate (2 x 30 mL). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo to give the title compound as a colorless oil (212mg, 44%).
Mass spectrum (API ⁺ ): Found 173 (MH ⁺ ). C ₁₁ H ₁₂ N ₂ requires 172.
¹ H NMR (CDCl ₃ ) δ: 2.04 (1H, br s), 2.95 (8H, m), 7.18 (1H, d, J = 8 Hz), 7.38 (2H, m) ,

Description 11

7-acetyl-trans-3- (2- (1- (4-N-tert-butoxycarbonyl) amino) cyclohexyl) ethyl-2,3,4,5-tetrahydro-1H-3-benzazepine

• Mass spectrum (API ⁺ ): Found 415 (MH ⁺ ). C ₂₅ H ₃₈ N ₂ O ₃ requires 414.

Description 12

7-acetyl-trans-3- (2- (1- (4-amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine

• Mass spectrum (API ⁺ ): Found 315 (MH ⁺ ) C ₂₀ H ₃₀ N ₂ O requires 314.
• ¹ H NMR (CDCl ₃ ) δ: 0.80-1.30 (5H, m), 1.41 (4H, m), 1.65-1.85 (4H, m), 2.48 (2H, m), 2.57 (3H, s), 2.60 (5H, m), 2.97 (4H, m), 7.17 (1H, d, J = 8 Hz), 7.70 (2H, m).

Description 13

7-acetyl-3- (tert-butyloxycarbonyl) -2,3,4,5-tetrahydro-1H-3-benzazepine

To a stirred solution of 3- (tert-butyloxycarbonyl) -7-trifluoromethylsulfonyloxy-2,3,4,5-tetrahydro-1H-3-benzazepine (10 g, 25.3 mmol) in anhydrous dimethylformamide (100 mL) was added Argon at room temperature, successively triethylamine (7.05 mL, 50.6 mmol), butyl vinyl ether (16.4 mL, 126.6 mmol), 1,3-bis (diphenylphosphino) propane (0.412 g, 1 mmol) and palladium acetate (0.202 g, 0.9 mmol). The resulting reaction mixture was heated at 85 ° C. for 1 h and cooled to room temperature. 4% aqueous hydrochloric acid (150 ml) was added and stirring was continued for 0.5 h. The reaction mixture was extracted with dichloromethane (3 x 300 ml) and the combined organic phases were washed with water (4 x 500 ml), dried (Na ₂ SO ₄ ) and evaporated under vacuum to give a brown gum. Chromatography on silica gel eluting with a 0-30% ethyl acetate-hexane gradient gave the title compound as a colorless solid (5.8 g, 79%).
¹ H NMR _(CDCl3) δ: 1.49 (9H, s), 2.58 (3H, s), 2.96 (4H, m), 3.57 (4H, m), 7.21 (1H , d, J = 8 Hz), 7.72 (2H, m).

Description 14

7-acetyl-2,3,4,5-tetrahydro-1H-benzazepine

Preparation of 7-acetyl-3- (tert-butyloxycarbonyl) -2,3,4,5-tetrahydro-1H-3-benzazepine (6.3 g, 21.8 mmol) using the method of Description 10 gave Pale yellow oil (4.12 g, 100%).
¹ H NMR (CDCl ₃ ) δ: 1.89 (1H, s), 2.58 (3H, s), 2.97 (8H, s), 7.17 (1H, d, J = 8 Hz), 7.70 (2H, m).

Description 15

3- (3-bromophenyl) -5-methyl-1,2,4-oxadiazole

Potassium tert-butoxide (7.33 g, 65.4 mmol) was added to ice-cooled methanol over 5 minutes under argon. After a further 5 min, hydroxyamine hydrochloride (4.9 g, 70.43 mmol) was added in one portion and the resulting mixture was stirred at room temperature for 1 h. A solution of 3-bromobenzonitrile (7.93 g, 43.6 mmol) in methanol (120 mL) was added in one portion, the mixture was heated at reflux for 4 h and filtered cooled, and the filtrate was evaporated in vacuo. The residue was refluxed in acetic anhydride (60 ml) for 3 hours, cooled to room temperature and poured into ice-water (300 ml). The precipitate was filtered, washed with water, dried under vacuum and chromatographed on silica eluting with a 0-10% 0-30% ethyl acetate-hexane gradient. Fractions containing the desired product were combined and evaporated under vacuum, the residue was recrystallized from hexane to give the title compound as colorless crystals (5.2 g, 50%).
Mass Spectrum: (API ⁺ ) Found: 239 (MH ⁺ ). C ₉ H ₇ ⁷⁹ BrN ₂ O requires 238
¹ H NMR _(CDCl3) δ: 2.66 (3H, s), 7.36 (1H, t, J = 8 Hz), 7.63 (1H, m), 8.05 (1H, m), 8.23 (1H, m).

Description 16

3- (5-methyl-1,2,4-oxadiazol-3-yl) benzoic acid

A mixture of 3- (3-bromophenyl) -5-methyl-1,2,4-oxadiazole (2.68 g, 11.3 mmol), tributylamine (3.05 mL, 12.5 mmol) and trans-dibromobis (triphenylphosphine) palladium (II) (0.13 g, 0.16 mmol) in methanol (5 mL) was carbonylated at 30 psi and 100 ° C for 18 h. The mixture was cooled to room temperature, diluted with ethyl acetate (100 mL) and washed successively with saturated sodium bicarbonate solution (2 x 300 mL), brine (100 mL), 0.5 N hydrochloric acid (200 mL), brine (100 mL), then dried (Na ₂ SO ₄ ) and evaporated in vacuo to give a yellow oil (2.49 g). A sample of 2 g of this oil was dissolved in aqueous methanol (5: 3, 80 ml), to which was added sodium hydroxide (0.36 g), and the mixture was stirred at room temperature for 20 hours. The mixture was evaporated under vacuum and the residue was partitioned between ethyl acetate (100 ml) and water (100 ml). The aqueous layer was acidified with 2N HCl, the resulting precipitate was filtered, washed with water and dried under vacuum to give the title compound as a colorless solid (0.78 g, 42%).
Mass Spectrum: (API ⁺ ) Found: 205 (MH ⁺ ). C ₁₀ H ₈ N ₂ O ₃ requires 204.
¹ H NMR _(CDCl3) δ: 2.70 (3H, s), 7.71 (1H, m), 8.14 (1H, dd, J = 7.1 Hz), 8.23 (1H, dd , J = 7, 1 Hz), 8.54 (1H, m), 13.35 (1H, br s).

Description 17

3- (1-pyrazolyl) benzoic acid

A mixture of 3-hydrazine benzoic acid (1.52 g, 0.01 mmol) and malondialdehyde bis (dimethyl acetal) (2.39 mL, 0.01 mol) in ethanol (10 mL) and water (15 mL) was refluxed for 2 h heated. The resulting solution was cooled and evaporated to give the title product as a yellow solid (1.8 g, 96%).
¹ H NMR (DMSO-d ₆ ) δ: 6.60 (1H, t, J = 2 Hz), 7.65 (1H, t, J = 8 Hz), 7.81 (1H, d, J = 1 , 5 Hz), 7.89 (1H, dd, J = 8 and 1.5 Hz), 8.12 (1H, dd, J = 8 and 1.5 Hz), 8.4 (1H, d, J = 2 Hz), 8.64 (H, d, J = 2 Hz).
Mass spectrum (API ⁺ ): Found 189 (MH ⁺ ). C ₁₀ H ₈ N ₂ O ₂ requires 188.

Description 18

3- (tert-butoxycarbonyl) -7- (3- (5-methyl) -1,2,4-oxadiazolyl) -2,3,4,5-tetrahydro-1H-3-benzazepine

To a suspension of sodium methoxide (0.6 g, 11 mmol) in anhydrous methanol (12 mL) under argon was added hydroxylamine hydrochloride (0.76 g, 11 mmol), followed by 3- (tert-butyloxycarbonyl) -7- cyano-2,3,4,5-tetrahydro-1H-3-benzazepine (1.5 g, 5.5 mmol). The mixture was refluxed for 16 h and allowed to cool to room temperature. The methanol was evaporated in vacuo and the residue obtained was partitioned between dichloromethane (100 ml) and water (100 ml). The aqueous layer was washed with more CH ₂ Cl ₂ (100 ml). The combined organic extracts were dried and evaporated under vacuum to give a solid (1.8 g) which was mixed with acetic anhydride (15 ml) and heated to 120 ° C for 2 h. Excess acetic anhydride was evaporated in vacuo and the resulting oily residue was partitioned between CH ₂ Cl ₂ (250 mL) and saturated sodium bicarbonate solution (250 mL). The organic layer was washed with more sodium bicarbonate solution (200 ml), dried and evaporated to give an oil. Gravity chromatography on silica gel eluting with ethyl acetate in hexane gave the title compound as a colorless oil (3.2 g, 73%).
¹ H NMR _(CDCl3) δ: 1.49 (9H, s), 2.65 (3H, s), 2.96 (4H, m), 3.58 (4H, m), 7.22 (1H , d, J = 8 Hz), 7.80 (2H, m).

Description 19

7- (3- (5-Methyl) -1,2,4-oxadiazolyl) -2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of 3- (tert-butoxycarbonyl) -7- (3- (5-methyl) -1,2,4-oxadiazolyl) -2,3,4,5-tetrahydro-1H-3-benzazepine (1.2 g, 3.6 mmol) in CH ₂ Cl ₂ (15 mL) and trifluoroacetic acid (15 mL) was heated at reflux for 2 h. The solvent was evaporated in vacuo and the residue was partitioned between diethyl ether (50 ml) and water (50 ml). The aqueous layer was saturated with potassium carbonate and then extracted with CH ₂ Cl ₂ (2 x 100 mL). The combined organic extracts were dried and evaporated under vacuum to give the title compound as an oil (0.74 g, 88%).
Mass spectrum (API ⁺ ): Found 230 (MH ⁺ ). C ₁₃ H ₁₅ N ₃ O requires 229.
¹ H NMR (CDCl ₃ ) δ: 1.80 (1H, br s), 2.65 (3H, s), 2.90-3.00 (8H, m), 7.20 (1H, d, J = 8 Hz), 7.75-7.85 (2H, m).

Description 20

7- (3- (tert-butoxycarbonyl) -2,3,4,5-tetrahydro-1H-3-benzazepinyl) carboxamide

To a solution of 3-tert-butyloxycarbonyl-7-cyano-2,3,4,5-tetrahydro-1H-3-benzazepine (5.44 g, 20 mmol) cooled in an ice-bath was added potassium carbonate (0.4 g ) in water (1 ml), followed by the dropwise addition of 30% w / w hydrogen peroxide (2.4 ml). The resulting mixture was stirred at 5 ° C 5, then the ice bath was removed. After a further 5 minutes, water (100 ml) was added. The solid precipitate was collected by filtration and dried to give the title compound as a colorless oil (4.35 g, 75%).
¹ H NMR (CDCl ₃ ) δ: 1.48 (9H, s), 2.96 (4H, m), 3.56 (4H, m), 5.60-6.30 (2H, br d), 7.19 (1H, d, J = 8 Hz), 7.50-7.80 (2H, m).

Description 21

3- (tert-butoxycarbonyl) -7- (5- (3-methyl) -1,2,4-oxadiazolyl) -2,3,4,5-tetrahydro-1H-3-benzazepine

A mixture of 7- (3-tert-butoxycarbonyl) -2,3,4,5-tetrahydro-1H-3-benzazepinyl) carboxamide (4.29 g, 14.8 mmol) and N, N-dimethylacetamide dimethyl acetal (6 mL , 41 mmol) was heated to 125 ° C under argon. The methanol was removed from the reaction within 2 hours by means of a distillation condenser. The reaction mixture was further evaporated under vacuum to give a thick brown oily residue. To this residue was added dioxane (10 ml), 5 M sodium hydroxide (4 ml), hydroxylamine hydrochloride (1.4 g, 20 mmol) and 70% aqueous acetic acid (20 ml) in the order listed. The combined mixture was stirred at room temperature for 15 min then 1 h at 90 ° C. The mixture was treated with water (100 mL) and extracted with CH ₂ Cl ₂ (2 x 150 mL). The combined organic extracts were washed with saturated sodium bicarbonate solution (100 ml), dried and evaporated in vacuo to give an oil. Gravity chromatography on silica gel eluting with ethyl acetate in hexane gave the title compound as a colorless oil (3.9 g, 80%).
¹ H NMR _(CDCl3) δ: 1.49 (9H, s), 2.47 (3H, s), 2.98 (4H, m), 3.60 (4H, m), 7.27 (1 H , d, J = 8 Hz), 7.80-7.90 (2H, m).

Description 22

7- (5- (3-Methyl) -1,2,4-oxadiazolyl) -2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of 3- (tert-butoxycarbonyl) -7- (5- (3-methyl) -1,2,4-oxadiazolyl) -2,3,4,5-tetrahydro-1H-3-benzazepine (3.8 g, 11.6 mmol) in CH ₂ Cl ₂ (50 mL) and trifluoroacetic acid (12 mL) was heated at reflux for 2 hours. The solvent was evaporated in vacuo and the residue was partitioned between diethyl ether (200 ml) and water (200 ml). The aqueous layer was saturated with potassium carbonate and then extracted with CH ₂ Cl ₂ (3 × 200 mL). The combined organic extracts were dried and evaporated under vacuum to give the title compound as an oil (2.4 g, 91%).
Mass spectrum (API ⁺ ): Found 230 (MH ⁺ ). C ₁₃ H ₁₅ N ₃ O requires 229.
¹ H NMR (CDCl ₃ ) δ: 1.86 (1H, br s), 2.47 (3H, s), 3.00 (8H, m), 7.25 (11H, d, J = 8 Hz) , 7.80-7.90 (2H, m).

Description 23

trans-3- (2- (1- (4-N-tert-butyloxycarbonyl) amino) cyclohexyl) ethyl-7- (3- (5-methyl) -1,2,4-oxadiazolyl) -2,3,4 , 5-tetrahydro-1H-3-benzazepine

Preparation of 7- (3- (5-methyl) -1,2,4-oxadiazolyl) -2,3,4,5-tetrahydro-1H-3-benzazepine in a similar manner as in Description 2 gave a Yield of 96%.
Mass spectrum (API ⁺ ): Found 455 (MH ⁺ ). C ₂₆ H ₃₈ N ₄ O ₃ requires 454th
¹ H NMR _(CDCl3) δ: 0.90-1.10 (4H, m), 1.15-1.25 (1H, m), 1.38 to 1.47 (11H, m), 1, 73-1.85 (2H, m), 1.93-2.05 (2H, m), 2.40-2.55 (2H, m), 2.56-2.70 (7H, m), 2.90-3.05 (4H, m), 3.35 (1H, br s), 4.35 (1H, br s), 7.19 (1H, d, J = 8Hz), 7.75 -7.85 (2H, m).

Description 24

trans-3- (2- (1- (4-N-tert-butoxycarbonyl) amino) cyclohexyl) ethyl-7- (5- (3-methyl) -1,2,4-oxadiazolyl) -2,3,4 , 5-tetrahydro-1H-3-benzazepine

Preparation of 7- (5- (3-methyl) -1,2,4-oxadiazolyl) -2,3,4,5-tetrahydro-1H-3-benzazepine in a similar manner as in Example 2 gave a Yield of 94%.
Mass spectrum (API ⁺ ): Found 455 (MH ⁺ ). C ₂₆ H ₃₈ N ₄ O ₃ requires 454th
¹ H NMR (CDCl ₃ ) δ: 0.95-1.10 (4H, m), 1.23 (1H, br s), 1.40-1.50 (11H, m), 1.70-1 , 85 (2H, m), 1.95-2.10 (2H, m), 2.46 (3H, s), 2.46-2.52 (2H, m), 2.60-2.70 (4H, m), 2.90-3.60 (4H, m), 3.35 (1H, m), 4.35 (1H, m), 7.23 (1H, d, J = 8 Hz) , 7.80-7.90 (2H, m).

Description 25

trans-3- (2- (1- (4-Amino) cyclohexyl) ethyl) -7- (3- (5-methyl) -1,2,4-oxadiazolyl) -2,3,4,5-tetrahydro- 1H-3-benzazepine

The preparation of trans-3- (2- (1- (4-N-tert-butyloxycarbonyl) amino) cyclohexyl) ethyl 7- (3- (5-methyl) -1,2,4-oxadiazolyl) -2, 3,4,5-tetrahydro-1H-3-benzazepine in a similar manner as in Description 3 gave a yield of 100%.
Mass spectrum (API ⁺ ): Found 355 (MH ⁺ ). C ₂₁ H ₃₀ N ₄ O requires 354.
¹ H NMR (CDCl ₃ ) δ: 0.90-1.10 (4H, m), 1.40 (2H, br s), 1.12-1.25 (1H, m), 1.40-1 , 50 (2H, m), 1.70-1.80 (2H, m), 1.80-1.90 (2H, m), 2.40-2.50 (2H, m), 2.55 -2.70 (8H, m), 2.90-3.00 (4H, m), 7.19 (1H, d, J = 8Hz), 7.75-7.85 (2H, m).

Description 26

trans-3- (2- (1- (4-Amino) cyclohexyl) ethyl) -7- (5- (3-methyl) -1,2,4-oxadiazolyl) -2,3,4,5-tetrahydro- 1H-3-benzazepine

The preparation of trans-3- (2- (1- (4-N-tert-butyloxycarbonyl) amino) cyclohexyl) ethyl 7- (5- (3-methyl) -1,2,4-oxadiazolyl) -2, 3,4,5-tetrahydro-1H-3-benzazepine in a similar manner as in Description 3 gave a yield of 100%.
Mass spectrum (API ⁺ ): Found 355 (MH ⁺ ). C ₂₁ H ₃₀ N ₄ O requires 354.
¹ H NMR (CDCl ₃ ) δ: 0.90-1.30 (5H, m), 1.37-1.50 (2H, m), 1.64 (2H, br s), 1.70-1 , 95 (4H, m), 2.46 (3H, s), 2.46-2.70 (7H, m), 2.90-3.10 (4H, m), 7.24 (1H, d , J = 8 Hz), 7.80-7.90 (2H, m).

Description 27

3-acetyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of acetic anhydride (6.37 g, 0.062 mol) in dichloromethane (50 ml) was added dropwise at 0 ° C under argon to a stirred solution of 2,3,4,5-tetrahydro-1H-3-benzazepine (8, 35 g, 0.057 mol) and triethylamine (8.7 ml) in dichloromethane (50 ml). After stirring at room temperature for 18 h, water (80 ml) was added and the organic layer was separated. The organic layer was washed with 0.5 M hydrochloric acid (50 ml), saturated sodium bicarbonate solution (50 ml) and water (50 ml). washed and then dried (Na ₂ SO ₄ ). Evaporation of the solvent under vacuum gave the title compound as a yellow oil which solidified on standing (10.24 g, 95%).
¹ H NMR _(CDCl3) δ: 2.18 (3H, s), 2.85-3.00 (4H, m), 3.55-3.60 (2H, m), 3.72 to 3, 80 (2H, m), 7,10-7,20 (4H, m).
Mass spectrum AP ⁺ : Found 190 (MH ⁺ ). C ₁₂ H ₁₅ NO requires 189.

Description 28

3-acetyl-7-chlorosulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of 3-acetyl-2,3,4,5-tetrahydro-1H-3-benzazepine (4.0 g, 0.021 mol) in dichloromethane (25 ml) was added dropwise to a stirred solution under argon at -70 ° C from chlorosulfonic acid in dichloromethane (25 ml). After warming to room temperature, the reaction mixture was stirred for 18 h before being quenched in ice / water (200 mL). The resulting mixture was extracted with ethyl acetate (3x100ml), dried (Na ₂ SO ₄ ) and the solvent was evaporated in vacuo to give the title compound as a pale yellow solid (2.74g, 45%).
¹ H NMR: δ _(CDCl3): 2.21 (3H, s), 3.0 to 3.10 (4H, m), 3.60-3.70 (2H, m), 3.74 to 3 , 80 (2H, m), 7.35-7.40 (1H, m), 7.80-7.85 (2H, m).
Mass spectrum AP ⁺ : Found 288 & 290 (MH ⁺ ). C ₁₂ H ₁₄ NSO ₂ Cl requires 287 & 289.

Description 29

3-acetyl-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine

To a stirred solution of sodium sulfite (1.60 g, 12.6 mmol) and sodium bicarbonate (1.14 g, 13.56 mmol) in water (25 mL) was added 3-acetyl-7-chlorosulfonyl-2,3,4 Added 5-tetrahydro-1H-3-benzazepine (2.6 g, 9.04 mmol) in tetrahydrofuran (10 mL). The reaction mixture was then heated to 75 ° C for 2 h, cooled to 30 ° C, and then methyl iodide (2.8 mL, 45.20 mmol) was added. After stirring at 50 ° C for 24 hours, the reaction mixture was cooled to room temperature and partitioned between water (50 ml) and ethyl acetate (100 ml). The aqueous layer was then separated and further extracted with ethyl acetate (2 x 80 ml). The combined organic phases were dried (Na ₂ SO ₄ ) and the solvent was removed in vacuo to give the title compound as a pale yellow solid. (1.77 g, 73%).
¹ H NMR (CDCl ₃₎ 2.20 (3H, s), 2.99 to 3.05 (4H, m), 3.06 (3H, s), 3.61 to 3.64 (2H, m) , 3.73-3.77 (2H, m), 7.32-7.37 (1H, m), 7.7-7.75 (2H, m).
Mass spectrum AP ⁺ : Found 268 (MH ⁺ ). C ₁₃ H ₁₇ NSO ₃ requires 267.

Description 30

7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of 3-acetyl-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine (1.75 g, 6.55 mmol) in 5M hydrochloric acid was refluxed for 18 hours. The reaction mixture was then cooled to room temperature, basified with potassium carbonate to pH 12, and the solvent was evaporated in vacuo. The solid residue was then extracted with ethyl acetate (5 x 60 ml) and the combined organic phases were dried (Na ₂ SO ₄ ). The solvent was then evaporated in vacuo to give the title compound as a pale yellow oil (450 mg, 32%).
¹ H NMR (CDCl ₃ ) 1.88 (1H, br s), 2.95-3.13 (8H, m), 3.04 (3H, s), 7.25-7.30 (1H, d ), 7.65-7.72 (2H, m).
Mass spectrum AP ⁺ : Found 226 (MH ⁺ ). C ₁₁ H ₁₅ NSO ₂ requires 225.

Description 31

trans-3- (2- (1- (4- (N-tert-butyloxycarbonyl) amino) cyclohexyl) ethyl-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of 7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine (1.0 g, 4.67 mmol) and trans (1- (4-N-tert-butyloxycarbonyl) amino) Cyclohexylacetaldehyde (0.8 g, 3.34 mmol) in dichloroethane (20 mL) was stirred at room temperature for 5 min before sodium triacetoxyborohydride (0.95 g, 4.49 mmol) was added in one portion. After stirring at room temperature for 48 hours, the reaction mixture was partitioned between water (50 ml) and dichloromethane (100 ml). The aqueous layer was separated, extracted again with dichloromethane (2 x 50 ml) and the organic layers were dried (Na ₂ SO ₄ ). The solvent was then evaporated in vacuo to give a pale yellow solid which was passed through Chromatography (silica gel; ethyl acetate: methanol, 9: 1) to give the title compound as a colorless solid (1.35 g, 90%).
¹ H NMR _(CDCl3): 0.99 to 1.14 (4H, m), 1.23-1.29 (1H, m), 1.41 to 1.46 (2H, m), 1.46 (9H, s), 1.73-1.79 (2H, m), 2.00-2.06 (2H, m), 2.50 (2H, t, J = 7.6 Hz), 2, 62-2.65 (4H, m), 2.99-3.02 (4H, m), 3.05 (3H, s), 3.38 (1H, br s), 4.38 (1H, br s), 7.27-7.30 (1H, d), 7.67-7.74 (2H, m).
Mass spectrum: AP ⁺ Found: 351 ([M-BOC] H ⁺ ). C ₂₄ H ₃₈ N ₂ SO ₄ requires 450.

Description 32

trans-3- (2- (1- (4-Amino) cyclohexyl) ethyl) -7-methylsulphonyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of trans-3- (2- (1- (4-N-tert-butyloxycarbonyl) amino) cyclohexyl) ethyl 7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine (1, 3 g, 2.89 mmol) in dichloromethane (24 mL) and trifluoroacetic acid (6 mL) was stirred at room temperature for 2 h. The reaction mixture was then concentrated under vacuum and the residue was partitioned between water (69 ml) and ethyl acetate (20 ml). The aqueous layer was separated, extracted with ethyl acetate (30 ml) and then basified to pH = 14 with 40% sodium hydroxide solution. The oily suspension was extracted with ethyl acetate (3 × 60 ml) and the combined organic phases were dried (Na ₂ SO ₄ ). The solvent was evaporated in vacuo to give the title compound as an off-white solid (1.01 g, 100%).
¹ H NMR (CDCl ₃ ) δ: 0.90-1.12 (4H, m), 1.15-1.22 (1H, m), 1.35-1.40 (2H, m), 1, 72-1.78 (2H, m), 1.82-1.90 (2H, m), 2.45-2.52 (2H, m), 2.55-2.62 (5H, m), 2.98-3.02 (4H, m), 3.04 (3H, s), 7.27 (1H, d, 7 = 7.8Hz), 7.56 (1H, s), 7.68 (1H, d).
Mass spectrum: AP ⁺ 351 (MH ⁺ ): C ₁₉ H ₃₀ N ₂ SO ₂ requires 350.

Description 33

3- (tert -butyloxycarbonyl) -7- (5- (3-methyl) isoxazolyl) -2,3,4,5-tetrahydro-1H-3-benzazepine

A mixture of 7-acetyl-3- (tert-butyloxycarbonyl) -2,3,4,5-tetrahydro-1H-3-benzazepine (6.18 g, 21.4 mmol) and dimethylacetamide dimethyl acetal (8 mL) became 125 ° C stirred. The by-product methanol was removed by a Dean-Stark apparatus. After 8 hours, excess dimethylacetamide dimethyl acetal was evaporated under vacuum to give a thick oily residue. Absolute ethanol (20 mL) and hydroxylamine hydrochloride (2.53 g, 36.4 mmol) were added and the resulting mixture was heated at reflux for 2 h. The ethanol was removed in vacuo and the remaining crude product residue was purified by chromatography on silica gel eluting with 10-100% ethyl acetate in hexane to give the title compound as a colorless oil (6.1 g, 87%).
Mass spectrum (API ⁺ ): Found 351 (MNa ⁺ ). C ₁₉ H ₂₄ N ₂ O ₃ requires 328.
¹ H NMR (CDCl ₃ ) δ: 1.49 (9H, s), 2.35 (3H, s), 2.90-3.00 (4H, m), 3.50-3.65 (4H, m), 6.31 (1H, s), 7.21 (1H, d, J = 8Hz), 7.50-7.53 (2H, m).

Description 34

7- (5- (3-methyl) isoxazolyl) -2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of 3- (tert-butyloxycarbonyl) -7- (5- (3-methyl) isoxazolyl) -2,3,4,5-tetrahydro-1H-3-benzazepine (5.1 g, 15.6 mmol) in CH ₂ Cl ₂ (30 mL) and trifluoroacetic acid (10 mL) was heated at reflux for 2 h. The solvent was evaporated in vacuo and the residue was partitioned between diethyl ether (150 ml) and water (150 ml). The aqueous phase was saturated with potassium carbonate and then extracted with CH ₂ Cl ₂ (2 × 200 ml). The combined organic extracts were dried and evaporated under vacuum to give the title compound (3.15 g, 88%).
Mass spectrum (API ⁺ ): Found 229 (MH ⁺ ). C ₁₄ H ₁₆ N ₂ O requires 228.
¹ H NMR (CDCl ₃ ) δ: 1.80 (1H, br s), 2.34 (3H, s), 2.90-3.10 (8H, m), 6.30 (1H, s), 7.17 (1H, d, J = 8Hz), 7.40-7.55 (2H, m).

Description 35

trans-3- (2- (1- (4-N-tert-butyloxycarbonyl) amino) cyclohexyl) ethyl-7- (5- (3-methyl) isoxazolyl) -2,3,4,5-tetrahydro-1H- 3-benzazepine

The preparation of 7- (5- (3-methyl) isoxazolyl) -2,3,4,5-tetrahydro-1H-3-benzazepine to a similar The manner as in Description 2 gave a yield of 92%.
Mass spectrum (API ⁺ ): Found 454 (MH ⁺ ). C ₂₇ H ₃₉ N ₃ O ₃ requires 453.
¹ H NMR (CDCl ₃ ) δ: 1.00-1.10 (4H, m), 1.15-1.25 (1H, m), 1.44 (9H, s), 1.55-1, 70 (2H, m), 1.70-1.85 (2H, m), 1.95-2.05 (2H, m), 2.34 (3H, s), 2.45-2.55 ( 2H, m), 2.55-2.70 (4H, m), 2.90-3.00 (4H, m), 3.35 (1H, m), 4.30-4.40 (1H, m), 6.30 (1H, s), 7.16 (1H, d, J = 8 Hz), 7.45-7.55 (2H, m).

Description 36

trans-3- (2- (1- (4-Amino) cyclohexyl) ethyl-7- (5- (3-methyl) isoxazolyl) -2,3,4,5-tetrahydro-1H-3-benzazepine

The preparation from trans-3- (2- (1- (4-N-tert-butyloxycarbonyl) amino) cyclohexyl) ethyl 7- (5- (3-methyl) isoxazolyl) -2,3,4,5-tetrahydro -1H-3-benzazepine in a similar manner as in Description 3 gave a yield of 99%.
¹ H NMR (CDCl ₃ ) δ: 0.90-1.10 (4H, m), 1.15-1.25 (1H, m), 1.35-1.50 (4H, m), 1, 70-1.80 (2H, m), 1.80-1.90 (2H, m), 2.34 (3H, s), 2.42-2.52 (2H, m), 2.55- 2.72 (5H, m), 2.90-3.00 (4H, m), 6.30 (1H, s), 7.16 (1H, d, J = 8Hz), 7.45-7 , 55 (2H, m).

Description 37

3- (tert-butyloxycarbonyl) -7-methanesulfonyloxy-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of 3- (tert-butyloxycarbonyl) -7-hydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine (3.0 g, 0.011 mol), methanesulfonyl chloride (1.44 g, 0.013 mol) Triethylamine (1.27 g, 0.013 mol) and dichloromethane (50 ml) were stirred at room temperature for 18 h. The reaction mixture was then partitioned between dichloromethane (50 ml) and a saturated sodium bicarbonate solution (50 ml). The organic layer was washed with water (50 ml) and then dried (Na ₂ SO ₄ ). The solvent was then evaporated in vacuo to give the title compound as a pale yellow oil (3.85 g, 99%).
¹ H NMR (CDCl ₃ ) δ: 1.48 (9H, s), 2.86-2.92 (4H, m), 3.13 (3H, s), 3.53-3.56 (4H, m), 7.00-7.03 (2H, m), 7.13-7.16 (1H, m).
Mass Spectrum (AP ⁺ ): Found 242 [M-BOC] H +. C ₁₆ H ₂₃ NSO ₅ requires 341.

Description 38

7-methanesulphonyloxy-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of 3- (tert-butyloxycarbonyl) -7-methanesulfonyloxy-2,3,4,5-tetrahydro-1H-3-benzazepine (3.8 g, 0.011 mol), trifluoroacetic acid (3.76 g, 0.033 mol) and dichloromethane (50 ml) was heated to 50 ° C for 5 h. The solvents were then evaporated in vacuo and the residue was partitioned between water (200 ml) and ethyl acetate (150 ml). The aqueous layer was removed and washed with ethyl acetate (100 ml) and then basified to pH = 14 with 40% sodium hydroxide solution. The suspension was extracted with ethyl acetate (3 × 150 ml) and the combined organic phases were dried (Na ₂ SO ₄ ). The solvents were evaporated in vacuo to give the title compound as a colorless oil (2.15 g, 80%).
¹ H NMR (CDCl ₃ ) δ: 2.88-3.00 (8H, m), 3.13 (3H, s), 6.99-7.03 (2H, m), 7.12 (1H, d).
Mass spectrum (AP ⁺ ): Found 242 (MH) ⁺ . C ₁₁ H ₁₅ NSO ₃ requires 241.

Description 39

trans-3- (2- (1- (4-N-tert-butyloxycarbonyl) amino) cyclohexyl) ethyl-7-methanesulphonyloxy-2,3,4,5-tetrahydro-1H-3-benzazepine

A mixture of 7- (methanesulfonyloxy) -2,3,4,5-tetrahydro-1H-3-benzazepine (2.0 g, 8.3 mmol) and trans-2- (1- (4-N-tert-butyl) Butyloxycarbonyl) amino) cyclohexylacetaldehyde (1.37 g, 5.7 mmol) in dichloroethane (30 mL) was stirred for 5 min at room temperature before sodium triacetoxyborohydride (1.69 g, 7.98 mmol) was added in one portion. After stirring at room temperature for 48 hours, a saturated sodium bicarbonate solution (50 ml) was added and the two layers were separated. The aqueous layer was extracted with dichloromethane (3x60ml) and the combined organic layers were dried (Na ₂ SO ₄ ). The solvent was evaporated in vacuo and the residue was purified by column chromatography (silica gel, ethyl acetate) to give the title compound as a white solid (2.54 g, 95%).
¹ H NMR _(CDCl3) δ: 0.9 to 1.25 (7H, m), 1.44 (9H, s), 1.70-1.80 (2H, m), 1.90 to 2, 05 (2H, m), 2.42-2.50 (2H, m), 2.55-2.65 (4H, m), 2, 88-2.95 (4H, m), 3.12 ( 3H, s), 3.36 (1H, br s), 4.34 (1H, br s), 6.98-7.02 (2H, m), 7.08-7.12 (1H, d) ,
Mass spectrum (AP ⁺ ): Found 467 [MH ⁺ ]. C ₂₄ H ₃₈ N ₂ SO ₅ requires 466.

Description 40

trans-3- (2- (1- (4-Amino) cyclohexyl) ethyl) -7-methanesulfonyloxy-2,3,4,5-tetrahydro-1H-3-benzazepine

A solution of trans-3- (2- (1- (4-N-tert-butyloxycarbonyl) amino) cyclohexyl) ethyl 7-methanesulfonyloxy-2,3,4,5-tetrahydro-1H-3-benzazepine, trifluoroacetic acid ( 8 ml) and dichloromethane (32 ml) was stirred at room temperature under argon for 2 h. The solvents were then evaporated in vacuo and the residue partitioned between water (150 ml) and ethyl acetate (60 ml). The aqueous layer was removed and washed with ethyl acetate (50 ml). The aqueous layer was then basified to pH = 14 with 40% sodium hydroxide solution. The suspension was extracted with ethyl acetate (3 x 80 ml) and the combined organic layers were dried (Na ₂ SO ₄ ). The solvents were evaporated in vacuo to give the title compound as an oil (1.78 g, 93%) which crystallized on standing.
¹ H NMR (CDCl ₃ ) δ: 0.95-1.45 (7H, m), 1.70-1.86 (2H, m), 1.80-1.90 (2H, m), 2, 49 (2H, t, J = 7.8 Hz), 2.55-2.65 (5H, m), 2.88-2.95 (4H, m), 3.12 (3H, s), 6 , 99-7.02 (2H, m), 7.11 (1H, d, J = 8 Hz).
Mass spectrum (AP ⁺ ): Found 367 (MH ⁺ ). C ₁₉ H ₃₀ N ₂ SO ₃ requires 366.

Examples

The compounds of Examples (Tables 1-3) listed below in the Tables were all prepared using the following general procedure:
A mixture of the appropriate trans-2- (2- (1- (4-amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine (0.35 mmol), the appropriate acid ( 0.35 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.35 mmol), 1-hydroxybenzotriazole (catalytic amounts) and dichloromethane (5 ml) was shaken for 16 h. Saturated sodium bicarbonate solution (4 ml) was then added and the mixture was shaken for 0.25 h. Chromatography of the organic layer over silicic acid with 50-100% ethyl acetate in hexane and 0-10% methanol in ethyl acetate in the form of gradient elution gave the title compounds.

Table 1

Table 2

Table 3

Table 4

The substituted benzazepines used as intermediates for the compounds Table 5 are required were from the compounds of Descriptions 8, 9 or 13 using standard procedures for the transfer of functional Groups and synthesis of heterocyclic rings or by palladium catalyzed cross-coupling reactions produced.

Table 5

Example 12

trans- (E) -7-Cyano-3- (2- (1- (4- (3- (4-fluoro) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- 3-benzazepine

A mixture of trans-3- (2- (1- (4-amino) cyclohexyl) ethyl) -7-cyano-2,3,4,5-tetrahydro-1H-3-benzazepine (103mg, 0.35mmol ), 4-fluorocinnamic acid (58 mg, 0.35 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (67 mg, 0.35 mmol) and 1-hydroxybenzotriazole (20 mg, 0.15 mmol). in dichloromethane (8 ml) was shaken at room temperature for 16 h. The reaction mixture was washed with saturated sodium bicarbonate solution (4 ml). The resulting precipitate was collected by filtration, washed with water (2 x 10 mL) and dried to give the title compound as a colorless solid (87 mg, 56%).
Mass spectrum (API ⁺ ): Found 446 (MH ⁺ ). C ₂₈ H ₃₂ FN ₃ O requires 445.
¹ H NMR (DMSO-d ₆ ) δ: 0.94-1.31 (8H, m), 1.81 (4H, m), 2.40 (5H, m), 3.04 (4H, m) , 3.63 (1H, m), 6.54 (1H, d, J = 16 Hz), 7.32 (4H, m), 7.59 (4H, m), 7.99 (1H, d, J = 8 Hz).

Example 13

trans-7-cyano-3- (2- (1- (4- (3-pyrrolo [2,3-b] pyridyl) carboxamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3 benzazepine

A mixture of trans-3- (2- (1- (4-amino) cyclohexyl) ethyl) -7-cyano-2,3,4,5-tetrahydro-1H-3-benzazepine (103mg, 0.35mmol ), 3-pyrrolo [2,3-b] pyridylcarboxylic acid (56 mg, 0.35 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (67 mg, 0.35 mmol) and 1-hydroxybenzotriazole ( 20mg, 0.15mmol) in dichloromethane (8mL) was shaken at room temperature for 16h. The reaction mixture was washed with saturated sodium bicarbonate solution (4 ml). The resulting precipitate was collected by filtration, washed with water (2 x 10 ml) and dried to give the title compound as a colorless solid (81 mg, 0.18 mmol, 53%).
Mass spectrum (API ⁺ ): Found 442 (MH ⁺ ). C ₂₇ H ₃₁ N ₅ O requires 441.
¹ H NMR (DMSO-d ₆ ) δ: 1.02 (2H, m), 1.15-1.45 (6H, m), 1.81 (4H, m), 2.50 (5H, m) , 2.91 (4H, m), 3.73 (1H, m), 7.14 (1H, m), 7.32 (4H, d, J = 8 Hz), 7.57 (2H, m) , 7.73 (1H, d, J = 8 Hz), 8.16 (1H, m), 8.25 (1H, m), 8.42 (1H, m), 12.03 (1H, br ).

Example 14

trans-7-cyano-3- (2- (1- (4- (3- (3- (5-methyl) -1,2,4-oxadiazolyl) benzoyl) amino) cyclohexyl) ethyl) -2,3, 4,5-tetrahydro-1H-3-benzazepine

A mixture of trans-3- (2- (1- (4-amino) cyclohexyl) ethyl-7-cyano-2,3,4,5-tetrahydro-1H-3-benzazepine (103 mg, 0.35 mmol) , 3- (3- (5-Methyl) -1,2,4-oxadiazolyl) benzoic acid (71mg, 0.35mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (67mg, 0, 35mmol) and 1-hydroxybenzotriazole (20mg, 0.15mmol) in dichloromethane (8ml) was shaken at room temperature for 16 hours The reaction mixture was washed with saturated sodium bicarbonate solution (4ml) The organic layer was pre-packed to 10g The fractions containing the title compound were combined and evaporated under vacuum to give the title compound as a colorless solid (119 mg, 71%).
Mass spectrum (API ⁺ ): Found 484. C ₂₉ H ₃₃ N ₅ O ₂ requires 483.
¹ H NMR (CDCl ₃ ) δ: 1.08-1.35 (5H, m), 1.45 (2H, m), 1.84 (2H, m), 2.12 (2H, m), 2 , 50 (2H, m), 2.62 (4H, m), 2.68 (3H, s), 2.96 (4H, m), 3.95 (1H, m), 6.02 (1H, d, J = 8 Hz), 7.17 (1H, d, J = 8 Hz), 7.41 (2H, m), 7.57 (1H, t, J = 8 Hz), 7.98 (1H , m), 8.17 (1H, m), 8.32 (1H, m).

Example 15

trans- (E) -7-Cyano-3- (2- (1- (4- (5-quinolinyl) carboxamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-benzazepine

A mixture of trans-3- (2- (1- (4-amino) cyclohexyl) ethyl) -7-cyano-2,3,4,5-tetrahydro-1H-benzazepine (0.10 g, 0.34 mmol), Quinoline-5-carboxylic acid (0.057 g, 0.37 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.065 g, 0.34 mmol), 1-hydroxybenzotriazole (catalytic amount), and dichloromethane (8 ml) was shaken for 16 h. Saturated sodium bicarbonate solution (4 ml) was added and the mixture was shaken for 0.25 h. Chromatography of the organic layer over silica eluting with a Gradients of 30-100% ethyl acetate in hexane and then 0-10% methanol in ethyl acetate gave the title compound (0.130 g, 86%).
Mass spectrum (API ⁺ ) Found 453 (MH ⁺ ). C ₂₉ H ₃₂ N ₄ O requires 452nd
¹ H NMR _(CDCl3) δ: 1.12 to 1.35 (5H, m), 1.41-1.51 (2H, m), 1.83 to 1.89 (2H, m), 2, 15-2.24 (2H, m), 2.48-2.55 (2H, m), 2.60-2.66 (4H, m), 2.91-2.99 (4H, m), 3.97-4.13 (1H, m), 5.86 (1H, d, J = 8Hz), 7.18 (1H, d, J = 8Hz), 7.37-7.49 (3H , m), 7.63-7.70 (2H, m), 8.15-8.20 (1H, m), 8.71-8.76 (1H, m), 8.94-8.96 (1H, m).

Example 16

trans- (E) -7-Cyano-3- (2 (1- (4- (3- (3-acetylamino) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- 3-benzazepine

A mixture of trans-3- (2- (1- (4-amino) cyclohexyl) ethyl) -7-cyano-2,3,4,5-tetrahydro-1H-3-benzazepine (0.10 g, 0, 34 mmol), 3-acetamidocinnamic acid (0.076 g, 0.42 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.071 g, 0.42 mmol), 1-hydroxybenzotriazole (catalytic amount) and dichloromethane (8 ml) was shaken for 16 h. Saturated sodium bicarbonate solution (4 ml) was added and the mixture was shaken for 0.25 h. The precipitated solid was filtered off and washed with water followed by diethyl ether and dried to give the title compound as a colorless solid (0.12 g, 74%).
Mass spectrum (API ⁺ ): Found 485 (MH ⁺ ). C ₃₀ H ₃₆ N ₄ O ₂ requires 484.
¹ H NMR (CDCl ₃ OD + CD ₃₎ δ: 1.02 to 1.35 (5H, m), 1.35-1.50 (2H, m), 1.77 to 1.82 (2H, m 2.00-2.04 (2H, m), 2.17 (3H, s), 2.47-2.55 (6H, m), 2.93-2.99 (4H, m), 1.77-1.82 (2H, (1H, m), 6.41 (1H, d, J = 15Hz), 7.17-7.30 (4H, m), 7.38-7.43 (3H, m), 7.50 (1H, d, J = 16 Hz), 7.80 (1H, s).

Example 17

trans-7-cyano-3- (2- (1- (4- (6- (3,4-dihydro-3-oxo) -2H-benzoxazinyl) carboxamido) cyclohexyl) ethyl) -2,3,4,5 tetrahydro-1H-benzazepine

A mixture of trans-3- (2- (1- (4-amino) cyclohexyl) ethyl) -7-cyano-2,3,4,5-tetrahydro-1H-3-benzazepine (0.10 g, 0, 34 mmol), 2,3-dihydro-3-oxo-4H-benzoxazine-6-carboxylic acid (0.072 g, 0.42 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.071 g, 0 , 42 mmol), 1-hydroxybenzotriazole (catalytic amount) and dichloromethane (8 ml) was shaken for 16 h. Saturated sodium bicarbonate solution (4 ml) was added and the mixture was shaken for 0.25 h. The precipitated solid was filtered off and washed with water followed by diethyl ether to give the title compound as a colorless solid (0.16 g, 100%).
Mass spectrum (API ⁺ ): Found 473 (MH ⁺ ). C ₂₈ H ₃₂ N ₄ O ₃ requires 472nd
¹ H NMR (DMSO-d ₆ ) δ: 0.95-1.50 (7H, m), 1.75-1.95 (4H, m), 2.40-2.65 (6H, m), 2.93-3.05 (4H, m), 3.69-3.82 (1H, m), 4.67 (2H, s), 7.02 (1H, d, J = 8Hz), 7 , 39 (1H, d, J = 8 Hz), 7.46-7.50 (2H, m), 7.65 (2H, m), 8.13 (1H, d, J = 8 Hz).

Example 18

trans- (E) -7-Cyano-3- (2- (1- (4- (3- (6- (1,2-dihydro-2-oxo) quinolinyl) propenoyl) amino) cyclohexyl) ethyl) -2 , 3,4,5-tetrahydro-1H-3-benzazepine

A mixture of trans -3- (2- (1- (4-amino) cyclohexyl) ethyl) -7-cyano-2,3,4,5-tetrahydro-1H-3-benzazepine (288 mg, 0.97 mmol ), trans-3- (6- (1,2-dihydro-2-oxo) quinolinyl) propenoic acid (250 mg, 1.16 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (204 mg , 1.07 mmol), 1-hydroxybenzotriazole (catalytic amount) and DMF (20 ml) was shaken for 18 h. Then, saturated sodium bicarbonate solution (8 ml) was added and the mixture was shaken for 0.25 h. The resulting solid was filtered and dried under vacuum to give the title compound as a colorless solid (370 mg, 77%).
Found: 495 (MH ⁺ ). C ₃₁ H ₃₄ N ₄ O ₂ requires 494.
¹ H NMR (DMSO-d ₆ ) δ: 0.94-1.05 (2H, m), 1.10-1.30 (3H, m), 1.30-1.40 (2H, m) 1 , 74-1.80 (2H, m), 1.80-1.88 (2H, m), 2.44 (2H, t, J = 7.5 Hz), 2.45-2.55 (4H , m), 2.85-2.95 (4H, m), 3.55-3.65 (1H, m), 6.50-6.60 (2H, m), 7.28-7.35 (2H, m), 7.40 (1H, d, J = 16 Hz), 7.55-7.60 (2H, m), 7.68-7.72 (1H, m), 7.81 ( 1H, s), 7.93 (1H, d, J = 16 Hz), 7.94-8.00 (2H, m).

Example 19

trans- (E) -7-Cyano-3- (2- (1- (4- (3- (2-fluoro-4-acetylamino) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5- tetrahydro-1H-3-benzazepine

A mixture of trans-3- (2- (1- (4-amino) cyclohexyl) ethyl) -7-cyano-2,3,4,5-tetrahydro-1H-3-benzazepine (150 mg, 0.51 mmol ), (E) - (2-fluoro-4-acetylamino) phenylpropenoic acid (113 mg, 0.51 mmol), EDC hydrochloride (97 mg, 0.51 mmol) and 1-hydroxybenzotriazole in dichloromethane (10 ml) was added Room temperature shaken for 16 h. The reaction mixture was washed with saturated aqueous sodium bicarbonate solution (4 mL) and the precipitate was collected by filtration then resuspended in water and filtered before being dried under vacuum to give the title compound as an off-white solid (200 mg, 79 %).
Mass spectrum (API ⁺ ): Found 503. C ₃₀ H ₃₅ FN ₄ O ₂ requires 502.
¹ H NMR δ (DMSO-d ₆ + TFA): 0.95-1.34 (5H, m), 1.61 (2H, m), 1.82 (4H, m), 2.07 (3H, s), 3.06 (2H, m), 3.18 (6H, m), 3.68 (3H, m), 6.59 (1H, d, J = 16 Hz), 7.34 (2H, m), 7.39-7.63 (3H, m), 7.72 (2H, m), 8.03 (1H, d, J = 8Hz), 9.74 (1H, br s), 10 , 29 (1H, s).

Example 20

trans- (E) -7-Cyano-3- (2- (1- (4- (3- (8- (1,2-dihydro-2-oxo) quinolinyl) propenoyl) amino) cyclohexyl) ethyl) -2 , 3,4,5-tetrahydro-1H-3-benzazepine

A mixture of trans-3- (2- (1- (4-amino) cyclohexyl) ethyl-7-cyano-2,3,4,5-tetrahydro-1H-3-benzazepine (0.25 g, 0.84 mmol), (E) -3- (8- (1,2-dihydro-2-oxo) quinolinyl) propenoic acid (0.27 g, 1.2 mmol), EDC hydrochloride (0.3 g, 1.5 mmol) and 1-hydroxybenzotriazole (50 mg) in DMF (10 ml) was stirred at 80 ° C for 4 h and then poured into water (500 ml) The precipitate was collected by filtration and then resuspended in an aqueous sodium bicarbonate solution The solid obtained was collected by filtration, then washed with water and diethyl ether and then dried under vacuum to give the title compound as a yellow solid (0.42 g, 95%).
Found: 495 (MH ⁺ ). C ₃₁ H ₃₄ N ₄ O ₂ requires 494.
δ (DMSO-d ₆ + TFA): 1.00-1.15 (2H, m), 1.15-1.30 (3H, m), 1.50-1.70 (2H, m), 1 , 70-1.85 (2H, m), 1.85-1.95 (2H, m), 2.95-3.30 (8H, m), 3.60-3.80 (3H, m) , 6.45-6.60 (2H, m), 7.23 (1H, t, J = 8Hz), 7.46 (1H, d, J = 8Hz), 7.60-7.80 ( 4H, m), 7.94 (1H, d, J = 10 Hz), 7.95-8.10 (3H, m), 9.70 (1H, br s).

Example 21

trans-7-cyano-3- (2- (1- (4- (5- (8-fluoro) quinolinyl) carboxamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine

A mixture of trans -3- (2- (1- (4-amino) cyclohexyl) ethyl) -7-cyano-2,3,4,5-tetrahydro-1H-3-benzazepine (0.162 g, 0.545 mmol), 8-Fluoroquinoline-5-carboxylic acid (0.115 g, 0.6 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.115 g, 0.6 mmol) and 1-hydroxybenzotriazole hydrate (0.01 g , 0.065 mmol) in dichloromethane (7 ml) was shaken for 18 h. Saturated aqueous sodium bicarbonate solution (6 ml) was added and shaking continued for 0.5 h. The organic layer was separated and pipetted onto a column of silica (10 g). Elution with a 30-100% ethyl acetate-hexane gradient and then a 1-10% methanol-ethyl acetate gradient gave the title compound as a colorless solid (0.22 g, 85%).
Mass spectrum (API ⁺ ): Found 471 (MH ⁺ ). C ₂₉ H ₃₁ FN ₄ O requires 470.
¹ H NMR (CDCl ₃ ) δ: 1.05-1.40 (5H, m), 1.45 (2H, m), 1.85 (2H, m), 2.20 (2H, m), 2 , 55 (2H, m), 2.63 (4H, m), 2.96 (4H, m), 4.00 (1H, m), 5.86 (1H, d, J = 8 Hz), 7 , 17 (1H, d, J = 8 Hz), 7.30-7.45 (3H, m), 7.54 (1H, m), 7.62 (1H, m), 8.80 (1H, d, J = 8 Hz), 9.01 (1H, m).

Example 22

trans-7-Acetyl-3- (2- (1- (4- (5-quinolinyl) carboxamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine

A mixture of 7-acetyl-trans-3- (2- (1- (4-amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine (0.105 g, 0.334 mmol), Quinoline-5-carboxylic acid (0.064 g, 0.368 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.071 g, 0.368 mmol) and 1-hydroxybenzotriazole hydrate (0.01 g, 0.065 mmol) in dichloromethane (6 ml) was shaken for 18 h. It was saturated aqueous sodium bicarbonate solution (6 ml) and shaking was continued for 0.5 h. The organic layer was separated and pipetted onto a column of silica (10 g). Elution with a 30-100% ethyl acetate-hexane gradient and then a 1-10% methanol-ethyl acetate gradient gave the title compound as a colorless solid (0.1 g, 64%).
Mass Spectrum (API ⁺ ): Found 470 (MH ⁺ ); C ₃₀ H ₃₅ N ₃ O ₂ requires 469.
¹ H NMR (CDCl ₃ ) δ: 1.10-1.40 (5H, m), 1.48 (2H, m), 1.86 (2H, m), 2.33 (2H, m), 2 , 55 (2H, m), 2.58 (3H, s), 2.65 (4H, m), 2.98 (4H, m), 4.02 (1H, m), 5.88 (1H, d, J = 8 Hz), 7.17 (1H, d, J = 8 Hz), 7.20 (1H, m), 7.55-7.75 (4H, m), 8.15 (1H, m), 8.75 (1H, d, J = 8 Hz), 8.95 (1H, m).

Example 23

trans-3- (2- (1- (4- (5- (2-methyl) quinolinyl) carboxamido) cyclohexyl) ethyl) -7-methylsulphonyl-2,3,4,5-tetrahydro-1H-3-benzazepine

A mixture of trans-3- (2- (1- (4-amino) cyclohexyl) ethyl) -7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine (100mg, 0.29mmol ), 2-methylquinoline-5-carboxylic acid (64 mg, 0.34 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (59 mg, 0.31 mmol) and 1-hydroxybenzotriazole (cat ) in dichloromethane (10 ml) was shaken at room temperature for 18 h. Then a saturated sodium bicarbonate solution (4 ml) was added and the mixture was shaken for 0.25 h. The organic layer was then applied directly to a silica column and eluted with a gradient of 30-100% ethyl acetate in hexane and then 0-10% methanol in ethyl acetate to give the title compound as a colorless solid (95 mg, 66%).
¹ H NMR δ (CDCl ₃₎ 1.15-1.30 (5H, m), 1.44 to 1.50 (2H, m), 1.82 to 1.88 (2H, m), 2.15 -2.20 (2H, m), 2.53 (2H, t, J = 7.6 Hz), 2.62-2.68 (4H, m), 2.75 (3H, s), 2, 98-3.02 (4H, m), 3.04 (3H, s), 3.95-4.05 (1H, m), 5.84 (1H, d, J = 8.2 Hz), 7 , 28 (1H, d, J = 7.9 Hz), 7.35 (1H, d, J = 8.8 Hz), 7.56-7.70 (4H, m), 8.08 (1H, d), 8.62 (1H, d).
Mass Spectrum: API ⁺ 520 (MH ⁺ ): C ₃₀ H ₃₇ N ₃ SO ₃ requires 519.

Example 24

trans-3- (2- (1- (4- (3- (3- (5-Methyl) -1,2,4-oxadiazolyl) benzoyl) amino) cyclohexyl) ethyl) -7-methylsulfonyl-2,3, 4,5-tetrahydro-1H-3-benzazepine

A mixture of trans-3- (2- (1- (4-amino) cyclohexyl) -7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine (100mg, 0.29mmol), 3- (3- (5-Methyl) -1,2,4-oxadiazolyl) benzoic acid (69 mg, 0.34 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (59 mg, 0; 31 mmol) and 1-hydroxybenzotriazole (cf amount) in dichloromethane (10 mL) was shaken at room temperature for 18 h, then a saturated sodium bicarbonate solution (4 mL) was added and the mixture was shaken for 0.25 h applied directly to a silica column and eluted with a gradient of 30-100% ethyl acetate in hexane and then 0-10% methanol in ethyl acetate to give the title compound as a colorless solid (103 mg, 69%).
¹ H NMR δ (CDCl _3): 1.08 to 1.30 (5H, m), 1.40 to 1.46 (2H, m), 1.80-1.85 (2H, m), 2, 08-2.15 (2H, m), 2.52 (2H, t, J = 7.8), 2.60-2.65 (4H, m), 2.68 (3H, s), 2, 98-3.02 (4H, m), 3.05 (3H, s), 3.90-4.00 (1H, m), 6.01 (1H, d, J = 8.0 Hz), 7 , 28 (1H, d, J = 7.28 Hz), 7.57 (1H, t, J = 7.8 Hz), 7.65-7.70 (2H, m), 8.0 (1H, d), 8.19 (1H, d, .J = 7.7 Hz), 8.32 (1H, s).
Mass spectrum: API ⁺ 537 (MH ^+): C ₂₉ H ₃₆ N ₄ SO ₄ requires 536th

Example 25

trans-7- (5- (3-Methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (3-pyrrolo [2,3-b] pyridyl) carboxamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride

A mixture of trans-3- (2- (1- (4-amino) cyclohexyl) -7- (5- (3-methyl) -1,2,4-oxadiazolyl) -2,3,4,5-tetrahydro 1H-3-benzazepine (21.0 g, 59.3 mmol), pyrrolo [2,3-b] pyridyl-3-carboxylic acid (10.57 g, 65.2 mmol), EDC hydrochloride (12.46 g, 64.4 mmol) and HOBT (0.5 g) in CH ₂ Cl ₂ (630 mL) and DMF (84 mL) was stirred at ambient temperature for 16 h. A saturated aqueous sodium bicarbonate solution (350 ml) was added and the mixture was stirred for 0.25 h. The precipitate was collected by filtration, washed successively with water and diethyl ether and dried under vacuum to give the free base of the title compound (18.0 g, 61%).
Mass spectrum (API ⁺ ): Found 499 (MH ⁺ ). C ₂₉ H ₃₄ N ₆ O ₂ requires 498th
NMR (DMSO-d ₆ ) δ: 0.90-1.10 (2H, m), 1.10-1.40 (5H, m), 1.70-1.90 (4H, m), 2, 40-2.70 (6H, m), 2.96 (3H, s), 3.31 (4H, m), 3.89 (1H, m), 7.15 (1H, m), 7.36 (1H, d, J = 8Hz), 7.71 (1H, d, J = 8Hz), 7.75-7.85 (2H, m), 8.12 (1H, s), 8.20 (1H, s), 8.35 (1H, d, J = 8 Hz), 12.02 (1H, br s).

To a suspension of the above free base (18.0 g, 36 mmol) in 10% methanol-dichloromethane (500 ml) became a 1 M solution of HCl in diethyl ether (37.08 ml). The resulting solution was evaporated under vacuum and the residue crystallized from methanol, whereby the title compound was obtained as a colorless solid (12.5 g, mp 275-276 ° C).

Example 26

trans- (E) -7- (3- (5-Methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (3- (4-fluoro) phenylpropenoyl) amino) cyclohexyl ) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine

alternative Name: (2E) -3- (4-fluorophenyl) -N- [traps-4- [2- [2,3,4,5-tetrahydro-7- (5-methyl-1,2,4-oxadiazole] 3-yl) -1H-3-benzazepin-3-yl] ethyl] cyclohexyl] -2-propenamide

A mixture of trans-3- (2- (1- (4-amino) cyclohexyl) ethyl) -7- (3- (5-methyl) -1,2,4-oxadiazolyl) -2,3,4,5 -tetrahydro-1H-3-benzazepine (0.1 g, 0.28 mmol), (E) -4-fluorocinnamic acid (0.046 g, 0.28 mmol), EDC hydrochloride (0.06 g, 0.31 mmol and HOBT (0.015 g) in dichloromethane (8 ml) was stirred at ambient temperature for 64 h and then washed with saturated aqueous sodium bicarbonate solution (4 ml). The organic phase was purified by chromatography on silica gel eluting 0-10% methanol in ethyl acetate to give the title compound as a colorless solid (0.12 g, 85%).
Mass Spectrum (API ⁺ ): Found 503 (MH ⁺ ). C ₃₀ H ₃₅ FN ₄ O ₂ requires 502.
NMR _(CDCl3) δ: 1.10-1.80 (4H, m), 1.25 (1H, m), 1.44 (2H, m), 1.78 (2H, m), 2.06 (2H, m), 2.50 (2H, m), 2.60-2.70 (7H, m), 2.90-3.00 (4H, m), 3.85 (1H, m), 5.39 (1H, d, J = 8Hz), 6.26 (1H, d, J = 16Hz), 7.05 (2H, t, J = 8Hz), 7.20 (1H, d, J = 8 Hz), 7.47 (2H, m), 7.57 (1H, d, J = 16 Hz), 7.80-7.90 (2H, m).

One Mixture of trans-3- (2- (1- (4-amino) cyclohexyl) ethyl) -7- (3- (5-methyl) -1,2,4-oxadiazolyl) -2,3,4,5- tetrahydro-1H-3-benzazepine (16.0 g, 0.045 mol), (E) -4-fluorocinnamic acid (7.5 g, 0.045 mol), EDC hydrochloride (9.53 g, 0.050 mol) and HOBT (0.78 g, 0.006 mol) in dichloromethane (0.78 L) was stirred under argon at ambient temperature for 111 h. It became a saturated aqueous sodium bicarbonate (1 L) was added, and after stirring for 0.25 h, the mixture was filtered and the solid with saturated aqueous sodium bicarbonate solution (2 x 0.25 l), Water (3 x 0.25 1) and diethyl ether (3 x 0.25 l) and dried under vacuum to give the title compound as a colorless solid (18.4 g, 81%).

The Filtrate was separated and the aqueous layer was washed with dichloromethane (2 x 0.3 l) extracted. The combined extracts were dried and placed under Vacuum evaporated to give a pale yellow solid (4.5 g). Successive trituration with dichloromethane (0.08 l), more saturated aqueous sodium bicarbonate (1 x 0.5 l; 2 × 0.2 l), water (3 x 0.2 1) and diethyl ether (3 x 0.2 1), followed by drying under vacuum to give the title compound as a colorless solid (2.8 g, 12%).

Both Batches had spectroscopic data similar to those above were identical.

To a solution of the above-obtained free base (21.2 g, 0.042 mol) in dichloromethane (0.55 l) and methanol (0.1 L) was added 1 M hydrochloric acid in diethyl ether (0.051 L, 0.05 mol). The resulting solution was evaporated under vacuum and the residue was crystallized from methanol to give (2E) -3- (4-fluorophenyl) -N- [trans-4- [2- [2,3,4,5-tetrahydro-7 - (5-methyl-1,2,4-oxadiazol-3-yl) -1H-3-benzazepin-3-yl] ethyl] cyclohexyl] -2-propenamide monohydrochloride was obtained as a colorless solid (19.8 g , 91%), mp. 259-261 ° C.
NMR (D ₆ -DMSO) δ: 1.00-1.09 (2H, m), 1.15-1.28 (3H, m), 1.60-1.70 (2H, m), 1, 70-1.80 (2H, m), 1.80-1.90 (2H, m), 2.66 (3H, s), 2.95-3.25 (6H, m), 3.35- 3.50 (2H, m), 3.55-3.75 (3H, m), 6.55 (1H, d, J = 16 Hz), 7.22-7.27 (2H, m), 7 , 39 (1H, d, J = 16 Hz), 7.40-7.45 (1H, m), 7.55-7.64 (2H, m), 7.80-7.85 (1H, m ), 7.87 (1H, s), 7.95-8.05 (1H, m), 10.60 (1H, br s).

Example 27

trans- (E) -7- (5- (3-Methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (3- (4-fluoro) phenylpropenoyl) amino) cyclohexyl ) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine

A mixture of trans-3- (2- (1- (4-amino) cyclohexyl) ethyl) -7- (5- (3-methyl) -1,2,4-oxadiazolyl) -2,3,4,5 -tetrahydro-1H-3-benzazepine (0.1 g, 0.28 mmol), (E) -4-fluorocinnamic acid (0.046 g, 0.28 mmol), EDC hydrochloride (0.06 g, 0.31 mmol and HOBT (0.015 g) in dichloromethane (8 ml) was stirred at ambient temperature for 64 h and then washed with saturated aqueous sodium bicarbonate solution (4 ml). The organic phase was purified by chromatography on silica gel eluting 0-10% methanol in ethyl acetate to give the title compound as a colorless solid (0.12 g, 85%).
Mass Spectrum (API ⁺ ): Found 503 (MH ⁺ ). C ₃₀ H ₃₅ FN ₄ O ₂ requires 502.
NMR _(CDCl3) δ: 1.10-1.30 (5H, m), 1.40 to 1.47 (2H, m), 1.78 to 1.82 (2H, m), 2,00- 2.10 (2H, m), 2.46 (3H, s), 2.47-2.52 (2H, m), 2.60-2.70 (4H, m), 2.95-3, 05 (4H, m), 3.86 (1H, m), 5.38 (1H, d, J = 8Hz), 6.26 (1H, d, J = 16Hz), 7.05 (2H, t, J = 8 Hz), 7.24 (1H, d, J = 8 Hz), 7.47 (2H, dd, J = 5.8 Hz), 7.57 (1H, d, J = 16 Hz ), 7.80-7.90 (2H, m).

Example 28

trans- (E) -7- (5- (3-Methyl) isoxazolyl) -3- (2- (1- (4- (3- (4-fluoro) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3 , 4,5-tetrahydro-1H-3-benzazepine

A mixture of trans -3- (2- (1- (4-amino) cyclohexyl) ethyl 7- (5- (3-methyl) isoxazolyl) -2,3,4,5-tetrahydro-1H-3-benzazepine (0.1 g, 0.28 mmol), 4-fluorophenylacetic acid (0.044 g, 0.28 mmol), EDC hydrochloride (0.065 g, 0.31 mmol) and HOBT (0.02 g) in CH ₂ Cl ₂ (8 mL) was stirred at ambient temperature for 16 h and then washed with saturated sodium bicarbonate solution (4 mL) The organic phase was purified by chromatography on silica gel eluting 0-10% methanol in ethyl acetate to give the title compound (0.1 g , 73%).
Mass spectrum (API ⁺ ): Found 490 (MH ⁺ ). C ₃₀ H ₃₆ FN ₃ O ₂ requires 489.
¹ H NMR δ (CDCl ₃ ): 0.90-1.10 (4H, m), 1.10-1.20 (1H, m), 1.30-1.40 (2H, m), 1, 70-1.80 (2H, m), 1.85-1.95 (2H, m), 2.34 (3H, s), 2.40-2.50 (2H, m), 2.55- 2.70 (4H, m), 2.90-3.00 (4H, m), 3.50 (2H, s), 3.65-3.80 (1H, m), 5.12 (1H, d, J = 8 Hz), 6.30 (1H, s), 7.03 (2H, t, J = 8 Hz), 7.15 (1H, d, J = 8 Hz), 7.19-7 , 25 (2H, m), 7.45-7.52 (2H, m).

Example 29

trans-7- (5- (3-Methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (4-fluoro) phenylacetamido) cyclohexyl) ethyl) -2,3,4 , 5-tetrahydro-1H-3-benzazepine

A mixture of trans-3- (2- (1- (4-amino) cyclohexyl) ethyl) -7- (5- (3-methyl) -1,2,4-oxadiazolyl) -2,3,4,5 -tetrahydro-1H-3-benzazepine (0.1 g, 0.28 mmol), (4-fluoro) phenylacetic acid (0.044 g, 0.28 mmol), EDC hydrochloride (0.054 g, 0.28 mmol) and HOBT (0.015 g) in dichloromethane (5 ml) was shaken at ambient temperature for 16 h and then saturated aqueous sodium bicarbonate solution (4 ml) was added. The organic phase was purified by chromatography on silica gel eluting with gradients of 30-100% ethyl acetate in hexane and then with 0-10% methanol in ethyl acetate to give the title compound as a colorless solid (0.095 g, 70%).
Mass spectrum (API ⁺ ): Found 491 (MH ⁺ ). C ₂₉ H ₃₅ FN ₄ O ₂ requires 490th
¹ H NMR δ (CDCl ₃ ): 0.90-1.30 (5H, m), 1.35-1.50 (2H, m), 1.70-1.80 (2H, m), 1, 85-1.95 (2H, m), 2.46 (3H, s), 2.40-2.50 (2H, m), 2.55-2.65 (4H, m), 2.95- 3.00 (4H, m), 3.50 (2H, s), 3.60-3.80 (1H, m), 5.13 (1H, d, J = 8Hz), 6.95-7 , 08 (2H, m), 7.15-7.30 (3H, m), 7.80-7.90 (2H, m).

Example 150

trans-3- (2- (1- (4- (5- (2-methyl) quinolinyl) carboxamide) cyclohexyl) ethyl) -7-methanesulfonyloxy-2,3,4,5-tetrahydro-1H-3-benzazepine

A mixture of trans-3- (2- (1- (4-amino) cyclohexyl) ethyl) -7-methanesulfonyloxy-2,3,4,5-tetrahydro-1H-3-benzazepine (150 mg, 0.41 mmol ), 2-methylquinoline-5-carboxylic acid (92 mg, 0.49 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (86 mg, 0.45 mmol) and 1-hydroxybenzotriazole (cat ) in dichloromethane (10 ml) was shaken at room temperature for 18 h. A saturated sodium bicarbonate solution (350 ml) was added and the mixture was shaken for 0.25 h. The organic layer was then applied directly to a silica column which was eluted with a gradient of 30-100% ethyl acetate in hexane and then 0-10% methanol in ethyl acetate to give the title compound as a colorless solid (161 mg, 74%). ).
¹ H NMR (CDCl ₃ ) δ: 1.15-1.30 (5H, m), 1.45-1.50 (2H, m), 1.82-1.90 (2H, m), 2, 15-2.20 (2H, m), 2.50-2.55 (2H, m), 2.60-2.68 (4H, m), 2.75 (3H, s), 2.90- 2.95 (4H, m), 3.13 (3H, s), 3.95-4.05 (1H, m), 5.82 (1H, d, J = 8.2 Hz), 7.00 -7.03 (2H, m), 7.12 (1H, d, J = 7.8 Hz), 7.35 (1H, d, J = 8.8 Hz), 7.55-7.70 ( 2H, m), 8.08 (1H, d, J = 8.3 Hz), 8.61 (1H, d).
Mass spectrum (AP ⁺ ): Found 536 (MH ⁺ ). C ₃₀ H ₃₇ N ₃ SO ₄ requires 535.

Claims (29)

Compound of the formula (I):

Formula (I) wherein: R ^{1 represents} a substituent selected from a hydrogen or halogen atom, a hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethanesulfonyloxy, pentafluoroethyl, C _1-4 alkyl, C _1-4 alkoxy, arylC _1-4 alkoxy, C _1-4 alkylthio, C _1-4 alkoxyC _1-4 alkyl, C _3-6 cycloalkylC _{1 -4} -alkoxy, C _1-4 alkanoyl, C _1-4 alkoxycarbonyl, C _1-4 alkylsulfonyl, C _1-4 alkylsulfonyloxy, C _1-4 alkylsulfonyl C _1-4 alkyl, arylsulfonyl, arylsulfonyloxy, arylsulfonylC _1-4 alkyl, C _1-4 alkylsulfonamido, C _1-4 alkylamido, C _1-4 alkylsulfonamidoC _1-4 alkyl, C _1-4 -alkylamido-C _1-4 -alkyl-, arylsulfonamido, arylcarboxamido, arylsulfonamido-C _1-4 -alkyl-, arylcarboxamido-C _1-4 -alkyl-, aroyl-, aroyl-C _1-4 alkyl or arylC _1-4 alkanoyl radical; a radical R ³ OCO (CH ₂ ) _p , R ³ CON (R ⁴ ) (CH ₂ ) _p , R ³ R ⁴ NCO (CH ₂ ) _p , or R ³ R ⁴ NSO ₂ (CH ₂ ) _p , where R Each of R ³ and R ⁴ independently represents a hydrogen atom or a C _1-4 alkyl radical, or R ³ R ^{4 forms} part of a C _3-6 azacycloalkane or C _3-6 (2-oxo) azacyloalkane ring and p represents zero or one whole Number from 1 to 4; or a group Ar ³ -Z, wherein Ar ^{3 represents} a phenyl ring or a 5- or 6-membered aromatic heterocyclic ring, each of which is optionally substituted with one or more substituents selected from hydrogen, halogen, amino, cyano, C _1-4 alkyl, C _1-4 alkylamino, C _1-4 dialkylamino, C _1-4 alkylamido, C _1-4 alkanoyl or R ⁵ R ⁶ NCO, wherein R ⁵ and R ⁶ each independently represent a hydrogen atom or a C _1-4 alkyl radical and Z represents a bond, O, S or CH ₂ , R ^{2 represents} a hydrogen atom or a C _1-4 alkyl radical; q is 1 or 2; A represents a group of formula (a), (b), (c) or (d);

wherein: Ar represents a phenyl ring or a 5- or 6-membered aromatic heterocyclic ring or a bicyclic ring system, all of which are independently optionally substituted with one or more substituents selected from a hydrogen or halogen atom or a hydroxy, oxo , Cyano, nitro, trifluoromethyl, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylenedioxy, C _1-4 alkanoyl, C _1-4 alkylsulfonyl, C _1-4 alkylsulfinyl, C _1-4 alkylthio, R ⁷ SO ₂ N (R ⁸ ) -, R ⁷ R ^B NSO ₂ -, R ⁷ R ⁸ N-, R ⁷ R ⁸ NCO- or R ⁷ CON (R ⁸ ) radical, wherein R ⁷ and R ⁸ each independently represent a hydrogen atom or a C _1-4 alkyl radical, or R ⁷ R ⁸ together form a C _3-6 alkylene chain and wherein in the ring Ar those Substituents ortho to each other optionally joined to form a 5- or 6-membered ring; Ar ¹ and Ar ² each independently represent a phenyl ring or a 5- or 6-membered aromatic heterocyclic ring, each independently optionally substituted with one or more substituents selected from a hydrogen or halogen atom or a hydroxy, oxo , Cyano, nitro, trifluoromethyl, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylenedioxy, C _1-4 alkanoyl, C _1-4 alkylsulfonyl, C _1-4 alkylsulfinyl, C _1-4 alkylthio, R ⁷ SO ₂ N (R ⁸ ) -, R ⁷ R ⁸ NSO ₂ -, R ⁷ R ⁸ N-, R ⁷ R ⁸ NCO- or R ⁷ CON (R ⁸ ) radical, wherein R ⁷ and R ^{8 are} as defined above; and in the ring Ar ^2, those substituents which are ortho to each other are optionally linked to form a 5- or 6-membered ring; and Y represents a bond, NHCO-, -CONH-, -CH ₂ - or - (CH ₂ ) _m Y ¹ (CH ₂ ) _n -, wherein Y ^{1 represents} O, S, SO ₂ or CO, and m and n each represent zero or 1 such that the sum of m + n is zero or one, with the proviso that when A represents a group of formula (a), any substituent present in Ar ortho to the carboxamide moiety will necessarily be hydrogen or is a methoxy group; r and s independently represent an integer of zero to 3 such that the sum of r and s is equal to an integer of 1 to 4; V represents a bond, O or S; or a salt of it. A compound or salt according to claim 1, wherein q represents 1. A compound or salt according to claim 1 or 2 wherein the rings Ar, Ar ¹ and Ar ^{2 are} each independently optionally substituted with a substituent as defined in claim 1. A compound or salt according to any one of claims 1 to 3, wherein A is the radical of formula (b). A compound or salt according to claim 4, wherein Ar ^{1 is} optionally substituted phenyl. A compound or salt according to claim 4 or 5, wherein Y is a bond. A compound or salt according to any one of claims 4, 5 or 6, wherein Ar ^{2 is} optionally substituted phenyl, pyridyl, pyrimidinyl, isoxazolyl, oxazolyl or oxadiazolyl. A compound or salt according to any one of claims 1 to 7, wherein R ¹ is defined as follows: (a) when R ^{1 is} an aryl C _1-4 alkoxy, arylsulfonyl, arylsulfonyloxy, arylsulfonylC _1-4 alkyl -, Arylsulfonamido, Arylcarboxamido, Arylsulfonamido-C _1-4 alkyl, Arylcarboxamido-C _1-4 alkyl, aroyl, Aroyl-C _1-4 alkyl or aryl-C _1-4 alkanoyl , the aryl moiety is selected from a phenyl ring or a 5- or 6-membered heterocyclic ring, each of which is optionally substituted with one or more substituents selected from hydrogen, halogen, amino, cyano, C _1-4 alkyl, C _{1- 4} -alkylamino, C _1-4 -dialkylamino, C _1-4 -alkylamido, C _1-4 -alkanoyl or R ⁵ R ⁶ NCO, wherein R ⁵ and R ⁶ each independently represent a hydrogen atom or a C _1-4 alkyl group ; and (b) in the radical R ¹ , an aryl moiety is optionally substituted with one or more substituents selected from hydrogen, halogen, amino, cyano, C _1-4 alkyl, C _1-4 alkylamino, C _1-4 dialkylamino , C _1-4 alkylamido, C _1-4 alkanoyl or R ⁵ R ⁶ NCO, wherein R ⁵ and R ⁶ each independently represent a hydrogen atom or a C _1-4 alkyl group. A compound or salt according to claim 8, wherein in the radical R ^{1 is} an aryl unit optionally with a as defined in claim 8, paragraph (b) substituent is substituted. A compound or salt according to any one of the preceding claims, wherein R ^{1 represents} a substituent selected from a halogen atom, a methyl, cyano, acetyl, trifluoromethyl, pentafluoroethyl, methylsulfonyl, methylsulfonyloxy or trifluoromethoxy radical or a radical Ar ³ - Z, wherein Z is a bond and Ar ^{3 is} a 5- or 6-membered heterocyclic ring optionally substituted with a methyl group containing at least one N and one O atom. A compound or salt according to any one of the preceding claims, wherein in the radicals Ar, Ar ¹ , Ar ² and Ar ³ each 5- or 6-membered heterocyclic aromatic ring, optionally substituted with one of the substituents defined in any one of the preceding claims, 1 to Contains 4 heteroatoms selected from O, N or S and, when the ring contains 2 to 4 heteroatoms, one is selected from O, N or S and the remaining heteroatom (s) is N. A compound or salt according to any one of the preceding claims, wherein R ^{2 is} a hydrogen atom. A compound or salt according to any one of the preceding Claims, wherein the compound or salt in the trans configuration in Relative to the cyclohexyl ring is present. Compound of formula (I) according to claim 1, namely: trans-3- (2- (1- (4- (4-quinolinyl) carboxamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine; trans- (E) -3- (2- (1- (4- (3- (3-Methylsulfonyl) -phenyl-propenoyl) -amino) -cyclohexyl) -ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine; trans- (E) -3- (2- (1- (4- (3- (4-fluoro) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine; trans-3- (2- (1- (4- (2-indolyl) carboxamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine; trans-3- (2- (1- (4- (3- (3-Pyridyl) phenyl) carboxamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine; trans-3- (2- (1- (4-Phenylacetamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine; trans-3- (2- (1- (4- (3-indolyl) acetamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine; trans-3- (2- (1- (4- (4-Quinolinyl) acetamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine; trans- (E) -3- (2- (1- (4- (3- (4-fluoro) phenylpropenoyl) amino) cyclohexyl) ethyl) -6-methoxy-2,3,4,5-tetrahydro-1H- -3-benzazepine; trans-6-methoxy-3- (2- (1- (4- (4-quinolinyl) carboxamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine; trans-6-methoxy-3- (2- (1- (4- (3-pyrrolo [2,3-b] pyridyl) carboxamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine; trans- (E) -7-Cyano-3- (2- (1- (4- (3- (4-fluoro) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine; trans-7-cyano-3- (2- (1- (4- (3-pyrrolo [2,3-b] pyridyl) carboxamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3 benzazepine; trans-7-cyano-3- (2- (1- (4- (3- (3- (5-methyl) -1,2,4-oxadiazolyl) benzoyl) amino) cyclohexyl) ethyl) -2,3, 4,5-tetrahydro-1H-3-benzazepine; or a salt of it. Compound of formula (I) according to claim 1 which is: trans- (E) -7-cyano-3- (2- (1- (4- (5-quinolinyl) carboxamido) cyclohexyl) ethyl) -2,3,4 , 5-tetrahydro-1H-3-benzazepine; trans- (E) -7-Cyano-3- (2- (1- (4- (3- (3-acetylamino) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine; trans -7-cyano-3- (2- (1- (4- (6- (3,4-dihydro-3-oxo) -2H-benzoxazinyl) carboxamido) cyclohexyl) ethyl) -2,3,4, 5-tetrahydro-1H-3-benzazepine; trans- (E) -7-Cyano-3- (2- (1- (4- (3- (6- (1,2-dihydro-2-oxo) quinolinyl) propenyl) amino) cyclohexyl) ethyl) -2 , 3,4,5-tetrahydro-1H-3-benzazepine; trans- (E) -7-Cyano-3- (2- (1- (4- (3- (2-fluoro-4-acetylamino) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5- tetrahydro-1H-3-benzazepine; trans- (E) -7-Cyano-3- (2- (1- (4- (3- (8- (1,2-dihydro-2-oxo) quinolinyl) propenoyl) amino) cyclohexyl) ethyl) -2 , 3,4,5-tetrahydro-1H-3-benzazepine; trans-7-cyano-3- (2- (1- (4- (5- (8-fluoro) quinolinyl) carboxamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine; trans-7-Acetyl-3- (2- (1- (4- (5-quinolinyl) carboxamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine; trans-3- (2- (1- (4- (5- (2-methyl) quinolinyl) carboxamido) cyclohexyl) ethyl) -7-methylsulphonyl-2,3,4,5-tetrahydro dro-1H-3-benzazepine; trans-3- (2- (1- (4- (3- (3- (5-Methyl) -1,2,4-oxadiazolyl) benzoyl) amino) cyclohexyl) ethyl) -7-methylsulfonyl-2,3, 4,5-tetrahydro-1H-3-benzazepine; trans-7- (5- (3-Methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (3-pyrrolo [2,3-b] pyridyl) carboxamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine; trans- (E) -7- (3- (5-Methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (3- (4-fluoro) phenylpropenoyl) amino) cyclohexyl ) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine; trans- (E) -7- (5- (3-Methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (3- (4-fluoro) phenylpropenoyl) amino) cyclohexyl ) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine; trans- (E) -7- (5- (3-Methyl) isoxazolyl) -3- (2- (1- (4- (3- (4-fluoro) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3 , 4,5-tetrahydro-1H-3-benzazepine; trans-7- (5- (3-Methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (4-fluoro) phenylacetamido) cyclohexyl) ethyl) -2,3,4 , 5-tetrahydro-1H-3-benzazepine; trans-7-cyano-3- (2- (1- (4- (2,5-difluoro) phenylacetamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine; trans-7-cyano-3- (2- (1- (2-naphthylacetamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine; trans- (E) -7-Cyano-3- (2- (1- (4- (3- (2,4-difluoro) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro- 1H-3-benzazepine; trans- (E) -7-Cyano-3- (2- (1- (4- (3- (2,5-difluoro) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro- 1H-3-benzazepine; trans- (E) -7-Cyano-3- (2- (1- (4- (3- (3-fluoro) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine; trans-7-cyano-3- (2- (1- (4- (3-phenylpropanoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine; trans- (E) -7-Cyano-3- (2- (1- (4- (3- (2-fluoro) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine; trans-7-cyano-3- (2- (1- (4- (8- (1,4-dihydro-4-oxo) quinolinyl) carboxamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro- 1H-3-benzazepine; trans-7-cyano-3- (2- (1- (4- (2-naphthyl) carboxamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine; trans- (E) -7-Cyano-3- (2- (1- (4- (3- (2-methoxy) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine; trans- (E) -7-Cyano-3- (2- (1- (4- (3- (3-methoxy) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine; trans- (E) -7-Cyano-3- (2- (1- (4- (3- (4-methoxy) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine; trans- (E) -7-Cyano-3- (2- (1- (4- (3- (2-acetyl) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine; trans- (E) -7-Cyano-3- (2- (1- (4- (3- (4-acetyl) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine; trans- (E) -7-Cyano-3- (2- (1- (4- (3- (2-cyano) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine; trans- (E) -7-Cyano-3- (2- (1- (4- (3- (3-cyano) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine; trans-7-cyano-3- (2- (1- (4- (3- (5- (3-methyl) isoxazolyl) benzoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1 H -3-benzazepine; trans-7-cyano-3- (2- (1- (4- (7- (1,2-dihydro-2-oxo) quinolinyl) carboxamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro- 1H-3-benzazepine; Trans- (Z) -7-cyano-3- (2- (1- (4- (3-phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine trans- (e) -7-cyano-3- (2- (1- (4- (3- (2-pyridyl) propenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3- benzazepine; Trans- (E) -7-cyano-3- (2- (1- (4- (3- (1- (4-fluoro) naphthyl) propenoyl) amino) cyclohexyl) ethyl) -2,3,4,5 tetrahydro-1H-3-benzazepine; trans- (E) -7-Cyano-3- (2- (1- (4- (3- (6-benzodioxanyl) propenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine; trans- (E) -7-Cyano-3- (2- (1- (4- (3- (3- (5-fluoro) indolyl) propenoyl) amino) cyclohexyl) ethyl) -2,3,4,5 tetrahydro-1H-3-benzazepine; trans- (E) -7-Cyano-3- (2- (1- (4- (3- (3- (1-methyl) benzimidazolyl) propenoyl) amino) cyclohexyl) ethyl) -2,3,4,5 tetrahydro-1H-3-benzazepine; trans- (E) -7-Cyano-3- (2- (1- (4- (3- (7-benzofuranyl) propenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine; trans- (E) -7-Cyano-3- (2- (1- (4- (3- (5- (3-methyl) indolyl) propenoyl) amino) cyclohexyl) ethyl) -2,3,4,5 -tetrahy dro-1H-3-benzazepine; trans- (E) -7-Cyano-3- (2- (1- (4- (3- (6- (2,3-dihydro-2-oxo) indolyl) propenoyl) amino) cyclohexyl) ethyl) -2 , 3,4,5-tetrahydro-1H-3-benzazepine; trans-7-cyano-3- (2- (1- (2-benzofuranylacetamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine; trans- (E) -7-Cyano-3- (2- (1- (4- (3- (4- (2-methyl) indolyl) propenoyl) amino) cyclohexyl) ethyl) -2,3,4,5 tetrahydro-1H-3-benzazepine; trans- (E) -7-Cyano-3- (2- (1- (4- (3- (5-benzimidazolyl) propenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine; trans- (E) -7-Cyano-3- (2- (1- (4- (3-phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine; trans- (E) -7-Cyano-3- (2- (1- (4- (3- (2,3-methylenedioxy) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro- 1H-3-benzazepine; trans- (E) -7-Cyano-3- (2- (1- (4- (3- (3- (1- (2-oxo) pyrrolidinyl)) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3 , 4,5-tetrahydro-1H-3-benzazepine; trans -7-cyano-3- (2- (1- (4- (2-indolylacetamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine; trans-7-cyano-3 - (2- (1- (4- (2-benzothiophenylacetamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine; trans- (E) -7-cyano-3- (2 - (1- (4- (3- (2- (3-bromo) thiophenyl) propenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine; trans-7-cyano -3- (2- (1- (4- (3- (2-pyridyl) benzoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine; trans-7-cyano -3- (2- (1- (4- (3- (5-pyrimidinyl) benzoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine; trans-7-cyano -3- (2- (1- (4- (3- (4-cyanophenyl) benzoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine; trans-7-cyano -3- (2- (1- (4- (3- (3- (5-ethyl) -1,2,4-oxadiazolyl) benzoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro -1H-3-benzazepine; trans- (E) -7-cyano-3- (2- (1- (4- (3- (2-thiophenyl) propenoyl) amino) cyclohexyl) ethyl) -2,3,4 , 5-tetrahydro-1H-3-benzazepine; trans- (E) -7-cyano-3- (2- (1- (4- (3- (2-furanyl) propenoyl) amino) cyclohexyl) ethyl) -2 , 3,4,5-tetrahydro-1 H -3-benzazepine; trans- (E) -7-Cyano-3- (2- (1- (4- (3- (3-thiophenyl) propenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine; trans- (E) -7-Cyano-3- (2- (1- (4- (3- (3-furanyl) propenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine; trans- (E) -7-Cyano-3- (2- (1- (4- (3- (4-quinolinyl) propenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine; trans- (E) -7-Cyano-3- (2- (1- (4- (3- (5-pyrimidinyl) propenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine; trans-7-cyano-3- (2- (1- (4- (2,4-difluoro) phenylacetamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine; trans-7-cyano-3- (2- (1- (4- (1-naphthyl) acetamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine; trans-7-Actyl-3- (2- (1- (4- (3-pyrrolo [2,3-b] pyridyl) carboxamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3 benzazepine; trans-7-Actyl-3- (2- (1- (4- (4-fluoro) phenylacetamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine; trans-7-Actyl-3- (2- (1- (4- (3- (3- (5-methyl) -1,2,4-oxadiazolyl) benzoyl) amino) cyclohexyl) ethyl) -2,3, 4,5-tetrahydro-1H-3-benzazepine; trans- (E) -7-Actyl-3- (2- (1- (4- (3- (4-fluoro) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine; trans-7-cyano-3- (2- (1- (4- (6- (2-amino) benzothiazolyl) acetamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine; trans -7-cyano-3- (2- (1- (4- (6- (2-methyl) benzothiazolyl) acetamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine; trans-7-cyano-3- (2- (1- (4- (6- (2,3-dihydro-2-oxo) indolyl) acetamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro- 1H-3-benzazepine; trans-7-cyano-3- (2- (1- (4- (5- (2,3-dihydro-2-oxo) indolyl) acetamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro- 1H-3-benzazepine; trans- (E) -7-Cyano-3- (2- (1- (4- (3- (4-methylaminocarbonyl) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3; 4,5-tetrahydro-1H- -3-benzazepine; trans-7-cyano-3- (2- (1- (4- (5- (2-amino) benzoxazolyl) acetamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine; trans-7-cyano-3- (2- (1- (4- (6- (1,2-dihydro-2-oxo) quinolinyl) acetamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro dro-1H-3-benzazepine; trans-7-cyano-3- (2- (1- (4- (7- (1,2-dihydro-2-oxo) quinolinyl) acetamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro- 1H-3-benzazepine; trans- (E) -7-Acetyl-3- (2- (1- (4- (3- (3-methoxy) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine; trans- (E) -7-Acetyl-3- (2- (1- (4- (3- (2-cyano) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine; trans- (E) -7-Acetyl-3- (2- (1- (4- (3- (3-thiophenyl) propenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine; trans- (E) -7-Acetyl-3- (2- (1- (4- (3- (8- (1,2-dihydro-2-oxo) quinolinyl) propenoyl) amino) cyclohexyl) ethyl) -2 , 3,4,5-tetrahydro-1H-3-benzazepine; trans-7-cyano-3- (2- (1- (4- (3- (1-pyrazolyl) benzoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine; trans-7-cyano-3- (2- (1- (4- (2-thiophenyl) acetamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine; trans-7-cyano-3- (2- (1- (4- (3-benzothiophenyl) acetamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine; trans-7-cyano-3- (2- (1- (4- (3- (2- (5-methyl) -1,3,4-oxadiazolyl) benzoyl) amino) cyclohexyl) ethyl) -2,3, 4,5-tetrahydro-1H-3-benzazepine; trans- (E) -7-Cyano-3- (2- (1- (4- (3- (2-naphthyl) propenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine; trans-7-acetyl-3- (2- (1- (4- (3-benzothiophenyl) acetamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine; trans- (E) -7-Acetyl-3- (2- (1- (4- (3- (4-acetamido) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine; trans-7-Acetyl-3- (2- (1- (4- (6- (2-amino) benzothiazolyl) acetamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine; trans-7-Acetyl-3- (2- (1- (4- (8- (1,4-dihydro-4-oxo) quinolinyl) carboxamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro- 1H-3-benzazepine; trans- (E) -7-Acetyl-3- (2- (1- (4- (3- (2-acetyl) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine; trans-7-Acetyl-3- (2- (1- (4- (2-benzothiophenyl) acetamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine; trans- (E) -7-Cyano-3- (2- (1- (4- (3- (5- (3-acetyl) indolyl) propenoyl) amino) cyclohexyl) ethyl) -2,3,4,5 tetrahydro-1H-3-benzazepine; trans-7-cyano-3- (2- (1- (4- (3- (5- (3-methyl) -1,2,4-oxadiazolyl) benzoyl) amino) cyclohexyl) ethyl) -2,3, 4,5-tetrahydro-1H-3-benzazepine; trans-7-cyano-3- (2- (1- (4- (5- (2-methyl) benzimidazolyl) acetamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine; trans-7-cyano-3- (2- (1- (4- (6-quinoxalinyl) acetamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine; trans- (E) -7-Cyano-3- (2- (1- (4- (3- (3- (2-acetyl) furanyl) propenoyl) amino) cyclohexyl) ethyl) -2,3,4,5 tetrahydro-1H-3-benzazepine; trans-7-cyano-3- (2- (1- (4- (6- (2-amino) benzoxazolyl) acetamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine; trans-7-cyano-3- (2- (1- (4- (6- (3,4-dihydro-2-oxo) -2H-benzoxazinyl) acetamido) cyclohexyl) ethyl) -2,3,4,5 tetrahydro-1H-3-benzazepine; trans- (E) -7-Cyano-3- (2- (1- (4- (3- (2-fluoro-5-acetamido) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5- tetrahydro-1H-3-benzazepine; trans-7- (5- (3-Methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (2-benzothiophenyl) acetamido) cyclohexyl) ethyl) -2,3,4 , 5-tetrahydro-1H-3-benzazepine; trans- (E) -7- (5- (3-Methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (3- (3-thienyl) propenoyl) amino) cyclohexyl ) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine; trans-7- (5- (3-Methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (5-quinolinyl) carboxamido) cyclohexyl) ethyl) -2,3,4 , 5-tetrahydro-1H-3-benzazepine; trans-7- (5- (3-Methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (3- (3- (5-methyl) -1,2,4 -oxadiazolyl) benzoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine; trans-7- (5- (3-Methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (8- (1,4-dihydro-4-oxo) quinolinyl) carboxamido ) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine; trans- (E) -7- (5- (3-Methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (3- (3-fluoro) phenylpropenoyl) amino) cyclohexyl ) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine; trans- (E) -7- (5- (3-Methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (3- (3-acetamido-2-fluoro) phenylpropenoyl ) amino) CYCLOHEPTA exyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine; trans- (E) -7- (5- (3-Methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (3- (3-acetyl) phenylpropenoyl) amino) cyclohexyl ) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine; trans-7- (5- (3-Methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (3-fluoro) phenylacetamido) cyclohexyl) ethyl) -2,3,4 , 5-tetrahydro-1H-3-benzazepine; trans-7- (5- (3-Methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (2,4-difluoro) phenylacetamido) cyclo-hexyl) ethyl) -2 , 3,4,5-tetrahydro-1H-3-benzazepine; trans-7- (5- (3-Methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (2-naphthyl) acetamido) cyclohexyl) ethyl) -2,3,4 , 5-tetrahydro-1H-3-benzazepine; trans-7- (5- (3-Methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (7- (3,4-dihydro-3-oxo) -2H- benzoxazinyl) carboxamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine; trans-7- (5- (3-Methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (5- (2-methyl) quinolinyl) carboxamido) cyclohexyl) ethyl) - 2,3,4,5-tetrahydro-1H-3-benzazepine; trans-7- (5- (3-Methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (2-fluoro) phenylacetamido) cyclohexyl) ethyl) -2,3,4 , 5-tetrahydro-1H-3-benzazepine; trans-7- (5- (3-Methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (2,5-difluoro) phenylacetamido) cyclohexyl) ethyl) -2,3 , 4,5-tetrahydro-1H-3-benzazepine; trans-7- (5- (3-methyl) -1,2, 4-oxadiazolyl) -3- (2- (1- (4- (2-indolyl) carboxamido) cyclohexyl) ethyl) -2,3,4 , 5-tetrahydro-1H-3-benzazepine; trans-7- (3- (5-Methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (2-benzothiophenyl) acetamido) cyclohexyl) ethyl) -2,3,4 , 5-tetrahydro-1H-3-benzazepine; trans- (E) -7- (3- (5-Methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (3- (3-thienyl) propenoyl) amino) cyclohexyl ) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine; trans-7- (3- (5-Methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (5-quinolinyl) carboxamido) cyclohexyl) ethyl) -2,3,4 , 5-tetrahydro-1H-3-benzazepine; trans-7- (3- (5-methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (3-pyrrolo [2,3-b] pyridyl) carboxamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine; trans-7- (3- (5-Methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (8- (1,4-dihydro-4-oxo) quinolinyl) carboxamido ) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine; trans-7- (3- (5-Methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (3- (3- (5-methyl) -1,2,4 -oxadiazolyl) benzoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine; trans- (E) -7- (3- (5-Methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (3- (3-fluoro) phenylpropenoyl) amino) cyclohexyl ) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine; trans- (E) -7- (3- (5-Methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (3- (2-fluoro) phenylpropenoyl) amino) cyclohexyl ) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine; or a salt of it. Compound of formula (I) according to claim 1 which is: trans-3- (2- (1- (4- (5- (2-methyl) quinolinyl) carboxamido) cyclohexyl) ethyl) -7-methanesulfonyloxy-2,3, 4,5-tetrahydro-1H-3-benzazepine; trans- (E) -3- (2- (1- (4- (3- (4-fluoro) phenylpropenoyl) amino) cyclohexyl) ethyl) -7-methylsulphonyl-2,3,4,5-tetrahydro-1H- -3-benzazepine; trans-3- (2- (1- (4- (3- (2- (4-methyl) oxazolyl) benzoyl) amino) cyclohexyl) ethyl) -7-methylsulphonyl-2,3,4,5-tetrahydro-1 H -3-benzazepine; trans-3- (2- (1- (4- (3-trifluoromethylbenzoyl) amino) cyclohexyl) ethyl) -7-methylsulphonyl-2,3,4,5-tetrahydro-1H-3-benzazepine; trans-3- (2- (1- (4- (5- (8-chloro-2-methyl) quinolinyl) carboxamido) cyclohexyl) ethyl) -7-methanesulphonyl-2,3,4,5-tetrahydro-1H- -3-benzazepine; trans-7- (5- (3-Methyl) isoxazolyl) -3- (2- (1- (4- (2-fluoro) phenylacetamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine; trans-7- (3- (5-Methyl) isoxazolyl) -3- (2- (1- (4- (4-fluoro) phenylacetamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine; trans- (E) -7- (2- (5-Methyl) oxazolyl) -3- (2- (1- (4- (3- (4-fluoro) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3 , 4,5-tetrahydro-1H-3-benzazepine; trans- (E) -7- (3- (5-Methyl) isoxazolyl) -3- (2- (1- (4- (3- (4-fluoro) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3 , 4,5-tetrahydro-1H-3-benzazepine; trans- (E) -7- (2-Pyridyl) -3- (2- (1- (4- (3- (4-fluoro) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5- tetrahydro-1H-3-benzazepine; Trans- (E) -7- (2-Pyrimidyl) -3- (2- (1- (4- (3- (4-fluoro) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5- tetrahydro-1H-3-benzazepine; trans- (E) -7- (1-pyrrolidinylcarbonyl) -3- (2- (1- (4- (3- (4-fluoro) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5- tetrahydro-1H-3-benzazepine; trans-7- (1-pyrrolidinylcarbonyl) -3- (2- (1- (4- (3-pyrrolo [2,3-b] pyridyl) carboxamido) cyclohexyl) ethyl) -2,3,4,5- tetrahydro-1H-3-benzazepine; trans- (E) -7- (5-pyrimidyl) -3- (2- (1- (4- (3- (4-fluoro) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5- tetrahydro-1H-3-benzazepine; trans-7- (5-pyrimidinyl) -3- (2- (1- (4- (3- (3- (5-methyl) -1,2,4-oxadiazolyl) benzoyl) amino) cyclohexyl) ethyl) - 2,3,4,5-tetrahydro-1H-3-benzazepine; trans-7- (5-pyrimidinyl) -3- (2- (1- (4- (5- (2-methyl) quinolinyl) carboxamido) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H- -3-benzazepine; trans-7- (3- (5-Methyl) isoxazolyl) -3- (2- (1- (4- (5- (2-methyl) quinolinyl) carboxamido) cyclohexyl) ethyl) -2,3,4,5 tetrahydro-1H-3-benzazepine; trans- (E) -7- (2-Pyridyl) -3- (2- (1- (4- (3- (2-cyano) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5- tetrahydro-1H-3-benzazepine; trans- (E) -7- (2-Pyridyl) -3- (2- (1- (4- (3- (3-cyano) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5- tetrahydro-1H-3-benzazepine; trans- (E) -7- (2-Pyridyl) -3- (2- (1- (4- (3- (4-cyano) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5- tetrahydro-1H-3-benzazepine; trans-3- (2- (1- (4- (5- (8-fluoro-2-methyl) quinolinyl) carboxamido) cyclohexyl) ethyl) -7-methylsulphonyl-2,3,4,5-tetrahydro-1H- -3-benzazepine; trans-3- (2- (1- (4- (5- (8-fluoro-2-methyl) quinolinyl) carboxamido) cyclohexyl) ethyl) -7-methylsulfonyloxy-2,3,4,5-tetrahydro-1H- -3-benzazepine; trans-3- (2- (1- (4- (3- (2- (5-Methyl) oxazolyl) benzoyl) amino) cyclohexyl) ethyl) -7-methylsulfonyloxy-2,3,4,5-tetrahydro-1 H -3-benzazepine; or a salt of it. A compound according to claim 1 which is trans-3- (2- (1- (4- (3- (3- (5-methyl) -1,2,4-oxadiazolyl) benzoyl) amino) cyclohexyl) ethyl) -7- methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a salt of it. A compound according to claim 1 which is trans-3- (2- (1- (4- (3- (2- (4-methyl) oxazolyl) benzoyl) amino) cyclohexyl) ethyl) -7-methylsulfonyl-2,3,4 , 5-tetrahydro-1H-3-benzazepine or a Salt of it. A compound according to claim 1 which is trans-3- (2- (1- (4- (3- (2- (5-methyl) oxazolyl) benzoyl) amino) cyclohexyl) ethyl) -7-methylsulfonyloxy-2,3,4 , 5-tetrahydro-1H-3-benzazepine or a salt of it. A compound according to claim 1, which is trans- (E) -7- (3- (5-methyl) -1,2,4-oxadiazolyl) -3- (2- (1- (4- (3- (4-fluoro ) phenylpropenoyl) amino) cyclohexyl) ethyl) -2,3,4,5-tetrahydro-1H-3-benzazepine, ie a compound of the formula:

or a salt of it. A process for the preparation of a compound or salt of formula (I) as defined in any one of claims 1 to 20, which process comprises: (a) reacting a compound of formula (II):

Formula (II) wherein R ¹ , R ² and q are as defined in any one of claims 1 to 20, with a compound of formula (III): A-COX Formula (III) wherein A is as defined in any one of claims 1 to 20 and X is a halogen atom or the residue of an activated ester; or (b) reacting a compound of formula (Π) with a compound A-Br or Al or A-OSO ₂ CF ₃ in the presence of carbon monoxide and a catalyst; or (c) to produce a compound of formula (I) wherein R ^{1 is} Ar ³ -Z and Z is a bond, reacting a compound of formula (IV):

Formula (IV) wherein A, R ² and q are as defined in any one of claims 1 to 13, 15, 16 or 20, a group R ^{1a represents} a group W, wherein W is a halogen atom or a trifluoromethylsulfonyloxy group, or W is a group M is selected from a boron derivative or a metal function, and when q is 2, the other R ^1a is R ¹ as defined in any one of claims 1 to 13, 15, 16 or 20; with a compound Ar ³ -W ¹ , wherein W ^{1 is} a halogen atom or a trifluoromethylsulfonyloxy group when W is M or W ^{1 is} M as defined above when W is halogen or trifluoromethylsulfonyloxy; or (d) to produce a compound of formula (I) wherein R ^{1 is} Ar ³ -Z and Z is O or S, reacting a compound of formula (V)

Formula (V) wherein A, R ² and q are as defined in any one of claims 1 to 13, one R ^{1b is} ZH and when q is 2 the other R ^1b is R ¹ as in any of the claims 1 to 13 is defined; with a reagent for introducing the residue Ar ³ ; or (e) to produce a compound of formula (I) wherein A is a radical of formula (b) and Y is a bond, reacting a compound of formula (VI):

wherein R ¹ , R ² , q and Ar ^{1 are} as defined in any one of claims 1 to 19 and W is as defined in (c) above, with a compound Ar ² -W ¹ , wherein W ^{1 is} a halogen atom or a trifluoromethylsulfonyloxy when W is M or W ^{1 is} M as defined in (c) above when W is halogen or trifluoromethylsulfonyloxy; or (f) converting a compound of formula (I) into another compound of formula (I) by, for example, (i) alkylating a compound of formula (I) wherein R ^{2 is} hydrogen, (ii) converting a residue R ¹ of Alkoxy (eg, methoxy) in hydroxy, (iii) converting the residue R ¹ from hydroxy to sulphonyloxy, for example, alkylsulfonyloxy or trifluoromethanesulfonyloxy, (iv) converting a compound in which Y is S into a compound wherein Y is SO ₂ , or (v) converting Y from CO to CH ₂ ; and / or (g) separating cis and trans isomers of the compounds of formula (I) by conventional methods; and optionally subsequently forming a salt of formula (I). A pharmaceutical composition comprising a compound of the formula (I) as in any of the claims 1 to 20, or a physiologically acceptable salt thereof and a physiologically compatible carrier for this. Use of a compound of formula (I), as in one of the claims 1 to 20, or a physiologically acceptable one Salt thereof, for the manufacture of a medicament for the treatment of a State which requires the modulation of a dopamine receptor. Use according to claim 23, wherein the dopamine receptor is a dopamine D ₃ receptor. Use according to claim 23 or claim 24, wherein a dopamine antagonist is needed becomes. Use of a compound of formula (I), as in one of the claims 1 to 20, or a physiologically acceptable one Salt thereof, for the manufacture of a medicament for the treatment of a psychotic state. Use according to claim 26, wherein the psychotic State schizophrenia is. Use of a compound of formula (I), as in one of the claims 1 to 20, or a physiologically acceptable one Salt thereof, for the manufacture of a medicament for the treatment of Substance abuse. Compound, namely: trans-3- (2- (1- (4- (N-tert-butyloxycarbonyl) amino) cyclohexyl) ethyl) -7-methylsulphonyl-2,3,4,5-tetrahydro-1H-3-benzazepine, or trans-3- (2- (1- (4-Amino) cyclohexyl) ethyl) -7-methylsulphonyl-2,3,4,5-tetrahydro-1H-3-benzazepine.